Abstract
Parkinson’s Disease (PD) is a progressive neurodegenerative disorder. Depression, a prevalent comorbidity across all stages, exacerbates PD severity. α-synuclein aggregation, the hallmark of PD, drives pathways overlapping with depression. This review places α-synuclein at the nexus of mechanistic synergy between PD and depression, and incorporates secondary analyses of genomic and transcriptomic datasets to identify convergent genes and pathways, underscoring depression’s potential as a biomarker for diagnosis and progression of PD.
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Introduction
Parkinson’s Disease (PD) is the second most common neurodegenerative disease (NDD) in the world, with physically debilitating symptoms1. Its cardinal features include tremors, bradykinesia, rigidity and postural instability due to the loss of dopaminergic (DA) neurons in the substantia nigra (SN) of the basal ganglia in the brain2. PD was first described by Dr. James Parkinson in 1817, and despite decades of research, the treatment approach remains symptomatic rather than curative3. The complex etiopathophysiology and the mechanisms of slowing PD progression are only partly understood. Aggregation of the α-synuclein (α-syn) protein or formation of Lewy bodies (LBs)/Lewy neurites (LNs) in SN and other parts of the brain remains the neuropathological hallmark of PD4. These aggregates are important drivers of neuroinflammation, oxidative stress, mitochondrial dysfunction and derangement of bioenergetics, ultimately resulting in apoptosis and neurodegeneration5,6. Notably, LBs transmit to other neurons and spread in the brain in a prion-like manner. Therefore, the α-syn accumulation seen in PD affects regions beyond the basal ganglia. The sequential spread of α-syn to various regions of the brain, starting from the lower brain stem to the cortex, correlates to the prodromal, clinical, and advanced stages of PD (7). Non-motor symptoms (NMS) occur at all stages of disease. In the prodromal stage, NMS can precede motor symptoms by one or two decades7.
Depression is a common prodromal feature of PD and may be one of the most underappreciated factors in the etiopathophysiology of PD. In fact, up to 40% of patients with PD have depression and 30% have anxiety8. Accumulating experimental evidence suggests that depression likely has a dual role, as both cause and consequence of PD. On the one hand, depression may be a direct consequence of α-syn pathology spreading into limbic and brainstem regions critical for mood regulation, including the raphe nuclei (RN), locus coeruleus (LC), and hippocampus. This spread occurs in the prodromal stage of PD, preceding the clinical stage/appearance of motor symptoms9. Unfortunately, PD is diagnosed approximately 1.5 years after the appearance of clinical motor symptoms when the patient has lost approximately 60% of irreplaceable dopaminergic neurons in SN10. Thus, depression as a prodromal feature is a potential biomarker for early diagnosis of PD. On the other hand, chronic psychological stress and hypothalamic-pituitary-adrenal (HPA) axis dysregulation can induce aggregation of α-syn11,12. Molecular markers of depression in association with α-syn pathology also disrupted neurotransmission, heightened inflammatory responses and apoptosis—mechanisms that converge with PD pathophysiology12,13,14. Depression worsens the severity of PD15. Again, depression is a potential biomarker for disease exacerbation/worsened severity. Appropriate and timely treatment plans can facilitate neuro-rescue. Taken together, depression as an NMS contributes to aetiology of PD and its exacerbation and/or progression through different stages. This dual role converges on α-syn. Thus, exploring the bidirectional relationship between depression and α-syn pathology not only deepens our understanding of PD aetiology but also highlights depression as a promising biomarker for early diagnosis and disease monitoring.
In this review, we summarize the interactions between α-syn and various molecular processes involved in depression that precede PD or aggravate the disease severity of patients diagnosed with PD. We also compile evidence that centres around LB neuropathology and the molecular markers of depression in the prodromal stage to delineate potential molecular signatures that may bridge the gap between the prodromal stage of PD and an early diagnosis. Finally, we offer novel insights from a secondary analysis conducted on publicly available genomic and transcriptomic datasets to narrow down convergent genes/pathways related to α-syn that may potentially be key in the mechanistic interplay of PD and depression.
α-synuclein neuropathology in PD
Physiological role of α-syn in the brain
α-syn is a 14 KDa, natively unfolded protein found in neurons, blood cells and other tissues. It is encoded by the SNCA gene. SNCA140, composed of 140 amino acid residues, is considered as the canonical isoform with the highest aggregation ability16. The positively charged N-terminus promotes interaction with lipidic membranes. Subsequent amino acid residues make up the aggregation-prone hydrophobic non-amyloid-ß component (NAC region). The negatively charged C-terminus of α-syn is involved in Ca2+ binding and chaperone-like activity17.
α-syn plays a role in vesicular trafficking, synaptic function, endocytosis and exocytosis. It is capable of sensing and stabilizing curved membranes by promoting the assembly of the SNARE complex, which is composed of presynaptic proteins that are involved in different phases of the exocytosis process18. Therefore, α-syn might be physiologically crucial to the functions of fast-firing neurons, such as the dopaminergic neurons in SN19.
Mechanisms of pathological changes in α-syn
Under normal physiological conditions, native α-syn is unfolded without a distinct tertiary structure. However, it can exist as stable tetramers that do not aggregate and remain water-soluble20. In PD, α-syn aggregates in the body of the neurons, forming LBs (when aggregated in neuronal stroma) or LNs (when aggregated in the axon). Many mechanisms have been suggested as a cause of the structural alterations that result in aberrant aggregation of α-syn in PD. These include phosphorylation of serine 129 (S129), ubiquitination, and truncation at the C-terminus of the protein. In fact, 90% of LBs are composed of phosphorylated-α-syn (p-α-syn)21. Indeed, in PD, α-syn adopts a pro-aggregation β-sheet conformation to facilitate the formation of oligomers and amyloid fibrils22. Furthermore, mutations in the α-syn encoding gene SNCA can lead to protein aggregation or interfere with its degradation. Additionally, gene duplication or triplication of wild-type (WT) SNCA can lead to increased risk of PD23,24. Aggregated α-syn promotes cytotoxic mechanisms, including neuroinflammation, mitochondrial dysfunction, impaired autophagy, ER stress, ROS production, and apoptosis. These molecular processes have been wonderfully reviewed by Forloni et al.25.
LB neuropathology in PD
LBs, primarily composed of p-α-syn, were found in the body of neurons in the post-mortem brain of patients with PD. Braak et al. described the stages of disease progression based on LB pathology in PD. The authors postulated that LB aggregation originates in the olfactory bulb and the autonomic enteric nervous system (ENS) in PD9. This is followed by a caudo-rostral (retrograde) spread of LB pathology over time, in which α-syn aggregates adopt a prion-like synaptic transmission to spread from ENS to the LC and RN via the dorsal motor nucleus of the vagus nerve (DMV), eventually (but not finally) transmitting to the SN pars compacta (SNpc). LB accumulation in the SNpc is associated with dopaminergic neuronal cell death and the characteristic clinical presentation of PD.
Braak’s staging (Fig. 1) classifies the spread of the above-mentioned LB pathology into six different stages, wherein advancing to each successive stage is indicative of PD progression. The transition from stage 1 to stage 2 reflects the spread of LB pathology from the DMV to the LC and RN. This phase represents the preclinical or prodromal stage of PD, accompanied by depression and other non-motor symptoms such as constipation and rapid eye movement (REM) sleep behaviour disorder, which can last for approximately a decade or more. Up to 90% of patients with PD experienced at least one NMS in the prodromal phase of disease in a cohort of n = 154. The highest prevalence and latency period belonged to sleep disorders (52.6%; 1.5 to 19.7 years). Constipation (24.7%; 1.3 to 18 years) and hyposmia (35.7%; 2.1 to 18 years) also showed considerable prevalence and latency periods. Neuropsychiatric symptoms (depressive symptoms, anxiety etc.) and cognitive impairments had considerable prevalence and a lower latency period (7.8% to 32.5%; 1.1 to 11 years)7. The latency period corresponds to the sequential spread of LBs from the ENS to LC and RN. Depression by itself can serve as a marker for prodromal PD. However, taking other prevalent NMS and their respective latency periods into account appears to be an improved strategy for early diagnosis of PD. Especially considering that most patients experience more than one NMS in the prodromal stage of disease. Specificity of using depression and other NMS as biomarkers can be enhanced using a selection of genes (discussed in subsequent sections).
A Trajectory of LB transmission across the brain at the sequential stages of PD and their phenotypic manifestations in patients. B Depression as a biomarker and/or potential therapeutic target at various disease stages in PD. Figure created in BioRender. Phansupkar, A. (2025) https://BioRender.com/aughpca.
LB pathology spreads to the SN pars compacta and amygdala in stages 3 and 4. Stage 3 is marked by the onset of motor symptoms and, therefore, is considered early clinical PD. Clinical diagnosis can take up to two years after the manifestation of motor symptoms. In advanced clinical PD, classified as stages 5 to 6, LB pathology can reach cortical neurons. This is accompanied by cognitive decline, emotional disturbances, psychosis and exacerbated motor dysfunction9.
An observational study of n = 1589 reported that the prevalence of NMS rose to >90% in advanced PD. In the early motor stages, sleep disturbances were the most frequent NMS (45.9% to 47.2%), followed by psychiatric manifestations like depression and anxiety (28.5% to 39.4%). In contrast, in advanced stages, psychiatric symptoms were predominant (52.2% to 73.3%), with sleep disorders ranking second (45.6% to 48%)26. This trajectory underscores that depression is not merely a comorbidity but a progressive feature of PD that exacerbates disease burden and may serve as a clinical indicator of advancing pathology.
The decade-long window between the prodromal and clinical stages of disease appears to be a missed opportunity. Prodromal features of PD, such as depression and the corresponding α-syn neuropathology, could potentially serve as early diagnostic markers or screening tools for PD. Depression can also persist or emerge during the advanced disease stages of PD. In the following sections, we summarize the literature that places α-syn at the nexus of both disease progression and symptom exacerbation, particularly in the context of depression - a common comorbidity in PD.
α-syn in depression
Recent evidence implicates α-syn in depression. Its involvement in synaptic impairment and neuro-inflammation correlates with depressive symptoms. α-syn transcripts were three-fold higher in the blood of patients with Major Depressive Disorder (MDD) (n = 36; p < 0.0001) when compared to matched controls27,28. Similar elevations were observed in the serum of MDD patients (n = 103; p < 0.001)29. However, these findings were not reproduced in cerebrospinal fluid (CSF)30. Du T. and colleagues provided mechanistic insights using an in-vivo model. The chronic restraint stress model of depression increased hippocampal α-syn in mice. Conversely, the overexpression of α-syn in the hippocampus induced depressive symptoms, loss of synaptic function genes VAMP2 and SYNTAXIN (both SNARE2 components), SYN1 and SYN2. Deletion of SNCA reversed these effects. α-syn in the hippocampus of mice also induced IL1-1β, IL-6, and TNF-α mediated gliosis and activated the complement system27. These findings highlight α-syn as a potential convergent node between PD pathophysiology and depression.
Interplay between α-syn and molecular mechanisms underlying PD and depression
Several key pathways represent points of convergence between PD and its most prevalent NMS - depression. These overlapping pathways include derangement of the HPA axis, impaired dopaminergic, serotonergic, and noradrenergic neurotransmission, increased oxidative stress, mitochondrial dysfunction, reduced trophic support, and neuroinflammation31,32,33. These overlaps likely reflect the sequential spread of LB pathology in the PD brain rather than random coincidence10. It remains unclear whether depression is a downstream consequence of α-syn pathology or a contributing factor to α-syn aggregation and disease progression. Current evidence supports a bidirectional relationship, where depression may both precede and exacerbate PD, forming a self-perpetuating cycle rather than a unidirectional effect. Therefore, investigating the interplay of α-syn with these molecular processes is imperative. Positioning α-syn at the nexus may help identify bridges to early PD diagnosis, with depression serving as a potential biomarker. It may also clarify correlations between depression in PD and disease exacerbation. The following sections summarize evidence supporting this concept.
HPA axis dysfunction
Physiological role of the HPA axis and downstream GC-GR signalling
The HPA axis regulates the body’s stress response and is activated during experiences of emotional or physical stress34. Stress activates hypothalamic hormones CRH and AVP, which stimulate pituitary ACTH, which drives the synthesis of stress hormone cortisol (CORT) in the adrenal glands35. CORT also provides negative feedback to the HPA axis by inhibiting the release of CRH, AVP and ACTH. This feedback mechanism regulates HPA axis activity and limits further CORT secretion. However, the type, duration and intensity of stressful conditions can cause overproduction of CORT, and subsequent hyperactivation of HPA34. In depression, this dysregulation is associated with altered neuropsychological deficits and hypercortisolemia36,37.
CORT, a glucocorticoid (GC), binds to two receptors: MR and GR. GR is engaged when basal concentrations of GCs are high (e.g., during experiences of stress)38. GRs act as transcription factors (TFs). Activated GRs can bind glucocorticoid response elements (GREs) in regulatory regions of target genes and modify their transcription. GRs also interact with other TFs and alter their transcriptional activity without directly interacting with DNA itself39,40. The GC/GR signalling exerts a protective effect under normal activation of the stress response. Going on to transcribe anti-inflammatory genes (eg: IL10) and repress inflammatory genes (e.g.,: TNFα, LITAF and IRF1)41,42,43. Importantly, the GC/GR complex transcribes FKBP5, which inhibits GR, acting as a negative feedback mechanism to the HPA axis stress response44. However, under pathological conditions, the GR sensitivity or bioavailability is often lessened. Thereby, the protective function of the pathway is attenuated; moreover, the HPA axis goes in overdrive and produces excessive CORT45 (Fig. 2). The GC/GR complex downregulates genes responsible for cell survival, such as BDNF46. GCs induce ROS production47. Such dysregulation creates a neurotoxic brain environment through inflammation, ROS production, and promotion of neurodegeneration.
Chronic psychological stress over-activates the HPA axis, resulting in hypercortisolemia. Under normal physiological conditions, HPA axis activation ends in the release of cortisol. Cortisol binds to glucocorticoid receptor (GR). GR translocates to the nucleus upon activation, modulating the transcription of genes associated with suppression of inflammation, cell survival and its own inhibitor FKBP5 (negative feedback to the HPA axis). Prolonged activation of HPA axis by chronic psychological stress ends in loss of GR and hypercortisolemia. Loss of GR leads to loss of neurotrophic support, neuroinflammation and HPA axis overactivity. Figure created in BioRender. Phansupkar, A. (2025) https://BioRender.com/qdvmv3k.
Derangement of the HPA axis in PD
HPA axis dysregulation is reflected consistently in increased serum/plasma cortisol levels of PD patients, while in a few reports, it was found to be lowered. CORT levels, whether increased or decreased, correlated poorly with motor function in PD patients48. This supports the notion that HPA axis dysfunction, a neurological event potentially preceding depression, contributes to disease progression or worsened disease outcomes in PD.
Dexamethasone suppressor test (DST) non-suppression marker of impaired GC feedback-was significantly more frequent in depressed (75%) than in nondepressed PD patients (27.7%)49. Additionally, PD non-suppressors showed elevated basal plasma ACTH and CORT50.
GR was downregulated in the SN of PD post-mortem brain (P ≤ 0.01) and mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [Pesticide that causes PD in humans]12. Although volumetric changes in the hippocampus and amygdala have been linked to depressive symptoms in PD, HPA axis dysfunction remains underexplored51,52,53. Yet, it is a critical pathway linking depression and PD progression.
Interaction of α-syn with the HPA axis
LRRK2 is another crucial gene for autophagy, vesicular trafficking and protein aggregation, which is strongly implicated in PD along with SNCA. Overexpression of LRRK2 can contribute to increased cytotoxicity, protein aggregation and increased levels of intracellular ROS54. GR, as a nuclear transcription factor, transactivated the expression of LRRK2 in the mouse DA neuronal cell line MN9D and hippocampal cells derived from rat55. A prevailing theory suggests synergy between LRRK2 and SNCA in the pathology of PD, indeed it has been shown that LRRK2 can exacerbate SNCA-led cytotoxicity and neurodegeneration in A53T α-syn transgenic mice56. Nevertheless, it is interesting to note that GR also transactivated SNCA in a ligand-dependent manner in the presence of synthetic CORT – dexamethasone (DEXA). Notably, no conserved GRE motifs were found in the promoter regions of either SNCA or LRRK2, so the mechanism of gene expression remains to be fully unravelled11. However, considering that CORT was elevated in most cohorts of PD, this association gives a possible hint to the CORT-mediated α-syn pathology11.
α-syn was overexpressed in hippocampal tissue from human PD brains12,57. This was accompanied by an imbalance in the GR/MR expression ratio. GR followed a trend of reduced expression, whereas MR was significantly upregulated in the human PD hippocampus12. This can be an underlying mechanism of HPA axis dysfunction and stress sensitivity in PD. Evidence of disturbed HPA axis function was also reported in a rat model of α-syn overexpression. CRH was downregulated in the hypothalamus of these rats, accompanied by a reduction in the weight of the adrenal glands and increased plasma CORT concentrations. Additionally, there were disturbances of noradrenaline release and DA turnover in the hypothalamus of α-syn overexpressing rats. Conversely, chronic CORT administration to α-syn overexpressing rats was associated with enhanced accumulation of pS129 α-syn in HPA axis regulatory centres; hypothalamus and hippocampus12.
A study conducted in rats has shown that administration of chronic CORT compromised the integrity of the nigrostriatal pathway, which is a dopaminergic tract (degenerated in PD) that connects the SN to the dorsal striatum, playing a crucial role in motor control; p-s129 α-syn pathology was exacerbated in SNpc along with a reduction in TH+ neurons. Unsurprisingly, chronic CORT treatment led to the phenotypic conversion of prodromal PD into overt PD with motor symptoms12. This points to the exacerbating effect of stress or depression on the progression of PD. Moreover, it supports the notion of depression and α-syn as synergistic biomarkers for early diagnosis.
Taken together, these findings suggest a bidirectional relationship between HPA axis dysfunction and α-syn pathology (Fig. 3). On one hand, GR activation can transactivate SNCA expression, thereby promoting α-syn accumulation and synergistic neurotoxicity. On the other hand, α-syn overexpression disrupts the HPA axis. These changes amplify stress sensitivity. Thus, HPA axis dysfunction and α-syn pathology potentially reinforce each other in a loop, whereby stress hormones drive α-syn accumulation, while α-syn in turn destabilizes HPA axis regulation, potentially increasing vulnerability to depression in PD and exacerbating disease symptoms.
(1) Chronic stress triggers HPA axis dysfunction and hypercortisolemia (2) Cortisol activates GR, a nuclear receptor, that translocates to the promoter of SNCA and LRRK2 and transactivates their expression (3) Elevated cortisol influences the accumulation and phosphorylation of α-syn (4) These changes are especially neurotoxic to motor neurons in the brain causing neurodegeneration and motor symptoms characteristic of PD (5) Accumulation of α-syn in hypothalamus and hippocampus exacerbates motor symptoms of PD and comorbidities like depression and cognitive impairments (6) The accumulation of α-syn in hypothalamus and hippocampus and accompanying hypercortisolemia both contribute to HPA axis dysfunction (7) This interaction between HPA axis and α-syn triggered by chronic stress provides one mechanistic bridge between the prodromal stage of PD - frequently accompanied by depression – and the clinical stage with overt motor symptoms. Figure created in BioRender. Phansupkar, A. (2025) https://BioRender.com/ikmcjky.
In another murine model employing exposure to chronic unpredictable stress (CUMS), phenotypic traits such as hypo locomotion during old age, anxiety, and elevated CORT metabolite levels were associated with SNCA overexpression. However, the accompanying disturbance in the gene expression profile of the processes neuroinflammation, Parkinson’s signalling, plasticity of striatal synapses, and to a lesser extent, hippocampal synapses was attributed to α-syn regardless of CUMS exposure58. Obtaining a corresponding proteomic profile is imperative to draw any concrete conclusion expounding the phenotype.
A study undertaken with 103 MDD patients described a relationship between α-syn and depression, in which serum α-syn levels were raised regardless of age29, hinting at a disturbance in the metabolism of α-syn in MDD that may potentially explain the bridge between prodromal PD and overt PD, strengthening the case for using α-syn and depression-related gene expression signatures as biomarkers for early PD diagnosis.
α-syn led disturbances in the neurotransmitter systems
Relationship between α-syn and serotoninergic system
Serotonin (5-HT) is an indole-derivative neurotransmitter that is particularly interesting in the context of the NMS of PD as it regulates mood, the sleep-wake cycle, cognition and memory59. Neurons producing 5-HT are primarily located in the RN of the brainstem. These neurons then connect to multiple regions of the brain, including cortex, hippocampus, thalamus, hypothalamus, amygdala, spinal cord and including the basal ganglia. The serotonergic system also comprises ~14 receptors and a 5-HT-specific transporter (SERT)59.
According to Braak staging hypothesis, α-syn pathology spreads from the ENS, olfactory nerve and DMV in stage 1, to the median RN and other regions of the lower brain stem in stage 2. Therefore, the appearance of α-syn pathology in the RN and possible 5-HT dysregulation precedes the spread of α-syn to the DA neurons in the SN during stage 3. This is supported by consistent reports of NMS in prodromal PD, followed by overt motor symptoms9,60.
Wilson H. and colleagues reported that premotor stage A53T SNCA carriers demonstrated significant loss of SERT binding in the striatum, brainstem and limbic regions of the brain In A53T SNCA carriers with PD, this loss spread to the hippocampus and cortex61. For premotor stage A53T SNCA carriers, loss of SERT binding was seen only in regions related to Braak stages 1 to 3 and this loss did not extend to regions associated with Braak stages 4 to 6, underscoring the role of RN α-syn pathology in prodromal NMS of PD. A 56% loss of serotonergic neurons was reported in the median RN of PD patients62. Similarly, a separate cohort of PD patients demonstrated 7–30% attenuation of SERT availability across the orbitofrontal cortex, caudate, putamen, and midbrain63.
Experimental models provide mechanistic insights into how α-syn drives serotonergic dysfunction. Overexpression of wild-type human α-syn in RN serotonergic neurons induced α-syn accumulation, phosphorylation, and aggregation. Mice overexpressing α-syn specifically showed impairments in BDNF production, 5-HT neurotransmission, and axonal pathology in RN projection areas. These changes translated into a depression-like phenotype. Importantly, antisense oligonucleotide-mediated suppression reduced α-syn synthesis in 5-HT neurons and prevented its accumulation in the forebrain. This treatment improved the behavioural phenotype and alleviated early deficits of 5-HT function64. These findings indicate that α-syn-mediated serotonergic dysfunction not only underlies depression-like phenotypes in PD but also precedes motor dysfunction.
Taken together, α-syn-mediated serotonergic dysfunction emerges as a critical convergence point between PD and depression. In PD, α-syn accumulation in the RN disrupts serotonergic projections to cortical and limbic circuits, manifesting as prodromal depressive symptoms. At the same time, α-syn-mediated reductions in BDNF and serotonergic signalling contribute to affective disturbances in PD. Therefore, α-syn pathology within the serotonergic system explains the high prevalence of depression in PD, highlights depression as an early clinical biomarker of PD. It also underscores α-syn as a central mechanistic nexus linking the two disorders.
α-syn and the disruption of dopaminergic transmission
Impaired dopaminergic transmission in the SN is a key feature of PD. This may be due to the death of DA-producing neurons, along with reduced expression of the dopamine transporters (DATs/SLC6A3), DA receptors and TH in surviving neurons. This is another shared pathway between PD and depression that may exacerbate disease severity when PD patients experience depression. In a meta-analysis of 38 neuroimaging studies that quantified striatal DA function, DAT availability was lower in the depression group in studies using DAT selective tracers (g = −0.56, p = 0.006). On the contrary, no significant differences were found in striatal D2/3 receptor availability or in combined dopamine synthesis and release capacity. However, it is important to acknowledge the specificity and off-target effects of radiotracers that may confound results in neuroimaging studies65. A complex interaction likely exists between α-syn, chronic psychological stress and DA neurotransmission in locomotor areas of the brain. In a murine model exposed to pre-formed fibrils of α-syn, chronic corticosterone treatment for up to 60 days increased α-syn aggregation and caused loss of DA neurons in the SN13. Chronic psychological stress by itself was associated with impaired motor activity and reduced binding site availability of DAT in the caudate nucleus, putamen and nucleus accumbens (locomotor regulation regions of the brain)66. Dalvi-Garcia F. colleagues developed a computational model that proposed cortisolemia-associated neurotoxicity due to increased production of dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) and serotonin metabolite 5-hydroxyindoleacetaldehyde, which contribute to α-syn aggregation and mitochondria fragmentation67.
Taken together, hypercortisolaemia may increase toxic DOPAL levels and therefore, vulnerability to α-syn accumulation. Conversely, α-syn aggregation within dopaminergic neurons disrupts dopamine neurotransmission, producing depressive phenotypes, thereby underscoring a reciprocal relationship between α-syn and depression in PD.
α-syn and other neurotransmitter disturbances (Norepinephrine)
Norepinephrine (NE), a neurotransmitter crucial to the cognitive, motor, and autonomic functions of the brain, is markedly reduced in the PD brain68. The CSF concentration of dopamine-β-hydroxylase (the rate-limiting enzyme for NE synthesis) is also diminished69. The LC in the brainstem is the primary source of NE. Therefore, when the α-syn pathology reaches the brainstem in early PD, NE deficiency can be expected in the prodromal stage. Neuroimaging reports were indicative of lower DAT and noradrenaline transporter (NAT) levels in the LC, and in several regions of the limbic system, including the anterior cingulate cortex, the thalamus, the amygdala, and the ventral striatum in depressed PD patients compared to patients with PD alone70. In fact, multiple clinical trials reported that the use of NE and SERT reuptake inhibitors in PD patients improved depressive but not motor symptoms71,72.
A recent in-silico work demonstrated that α-syn may participate in the folding of TH and dopamine β-hydroxylase, thereby inhibiting the biosynthesis of DA and NE. The authors suggested that inhibition of α-syn docking may enhance dopamine and NE biosynthesis, thereby alleviating PD symptoms73. However, this work lacked in vitro or in vivo validation. Jeannotte A. and colleagues reported that Norepinephrine Transporter (NET) activity and cell surface expression were decreased in cells co-transfected with NET and α-syn. However, this effect was reversed by a microtubule destabilizer, indicating that α-syn–microtubule interactions modulate NET activity and surface expression14. The same group of authors went on to validate the role of α-syn in the genesis of depression by NE disturbances using a Wistar–Kyoto rodent model, notable for their inherent depressive characteristics. In this model, the NET-selective antidepressant desipramine treatment reduced NET protein levels and increased α-syn levels. This modulation was interrupted by microtubule destabilizers, which solidified the role of α-syn in trafficking of NET away from the cell surface74. While these experiments were performed with native α-syn, it is interesting to hypothesize that the aberrant α-syn pathology in PD is disruptive to NE neurotransmission.
Therefore, α-syn led disturbances in NE neurotransmission may provide an opportunity for early diagnosis. Moreover, it is likely that α-syn–NE interactions underlie depression in PD and exacerbate PD progression, reinforcing a potential vicious cycle between the two diseases with α-syn as a focal point.
α-syn and increased neuroinflammation
Neuroinflammation is a key convergent pathway between PD and depression pathology. Post-mortem brain tissues from patients with either disease consistently showed elevated levels of inflammatory cytokines IFN-γ, IL-6, IL-1β and TNF-α75,76. In the context of this review, two interrelated mechanisms mediate this neuroinflammatory state: HPA axis dysfunction and glial cell activation.
GCs under normal conditions act via GRs to suppress inflammatory gene transcription in microglia and astrocytes. However, chronic stress and prolonged HPA axis activation cause GR downregulation, thereby removing this inhibitory checkpoint. Loss of GR function results in upregulation of pro-inflammatory cytokines and glial hyperactivation. Thus, HPA axis dysfunction and glial activation are part of an interconnected regulatory pathway that amplifies neuroinflammation.
GR, which is a master regulator of the inflammatory NFκB pathway. PT150, a modulator of GR, successfully attenuated the loss of DA neurons in SN in PD mice by inhibition of NFκB, subsequently reducing Iba-1+ microglia and GFAP+ astrocytes (markers of activated glia). PT150 enhanced p62-mediated degradation of p-α-syn by astrocytes and prevented the accumulation of p-α-syn in neurons, all of which collectively preserved TH + DA neurons in SN77. In the presence of α-syn aggregation, downregulation of microglial GR caused severe loss of TH+ neurons in the basal ganglia due to impaired GR-mediated regulation of TLR9. Conversely, GR knockout in the absence of α-syn aggregation did not significantly reduce TH+ neurons in the SN, underscoring a critical interplay of GR and α-syn in PD etiopathophysiology78. Exacerbated dyskinesia and DA neuron death were reported in a group of mice exposed to CUMS induced depression followed by MPTP treatment. The authors reported that depression activated microglial receptor P2X7R, triggering downstream activation of neuroinflammatory markers caspase-1, NLRP3 and IL-1β79. It is also important to note that the P2X7R has binding sites for α-syn, and this interaction becomes pathological in PD, leading to mitochondrial dysfunction and neuroinflammation80,81. Therefore, it can be hypothesized that the α-syn interaction with the P2X7R pathway is crucial in synergistic exacerbation of PD when the patient experiences depression. Further evidence comes from Valera E. and colleagues, who reported that antidepressants inhibit NFκB signalling, reduce IL-1β, and decrease α-syn propagation in transgenic animals expressing human α-syn82. Taken together, these findings reinforce that α-syn-associated neuroinflammation is potentiated by HPA axis dysfunction and stress, creating a mechanistic bridge between depression and PD progression.
α-syn and altered synaptic plasticity
GCs and α-syn appear to converge on dopaminergic synaptic plasticity, lowering the threshold for maladaptive signalling. This interplay may underlie the emergence of affective symptoms in prodromal PD while simultaneously priming neural circuits for accelerated motor decline. In an Oxidopamine (6-OHDA) induced PD rat model, researchers examined the effects of unilateral dopamine depletion, stress, and corticosterone on dopamine-related stress markers and neural plasticity. Stress and corticosterone both individually increased calcyon, a protein involved in clathrin-mediated endocytosis of D1 receptors, in the motor cortex and striatum in lesioned hemispheres in rats, thereby altering the availability of D1 receptors at the post-synaptic membrane. Synaptophysin, a constituent protein of synaptic vesicle membrane essential for vesicle fusion and neurotransmitter release, was downregulated in SN and VTA neurons following psychological stress after 6-OHDA lesions83. On the other hand, α-syn, through its chaperone functions, also plays an important role in dopamine-related synaptic plasticity. Somayaji M. and colleagues reported the dual role of α-syn in regulating DA release in the SN. The study showed that α-syn contributed to the alteration of synaptic plasticity at the presynaptic terminals in an activity-dependent manner. Short bursts produced rapid presynaptic facilitation, while prolonged burst activity slowly reduced DA release84. No studies have yet explored whether GC/GR signalling mediates the relationship between altered synaptic plasticity and α-syn. Further investigations are warranted to delineate any convergent mechanisms that may exacerbate disease progression or drive phenotypic changes from prodromal to overt PD.
α-syn and derangement in cellular bioenergetics/mitochondrial dysfunction
Mitochondrial dysfunction and impaired cellular bioenergetics form a crucial bridge between depression and the exacerbation of PD-related neurodegeneration. Recently, in an in-vitro model of mouse SN4741 neuronal cells, co-incubation of dopaminergic neurons with CORT and MPP+ led to a significant increase in ROS and neurodegeneration when compared to incubation with MPP+ alone. Similarly, total antioxidant pool, advanced oxidation of protein products, oxygen consumption rate (OCR) and oxygen production by mitochondrial ATP were significantly decreased when compared to incubation with MPP+ alone85. Psychological distress phenocopied brain mitochondrial dysfunction and motor deficits in a PINK1-KO rat model of PD. Male PINK KO rats demonstrated reduced mitochondrial OCR, TOM20 (marker of mitochondrial content), the antioxidants DJ1 and SOD2 in the pre-frontal cortex upon psychological distress. In SN, reduced expression of SOD2, CAT, TOM20 and BDNF was reported along with an increased mitochondrial OCR, all of which correlated with worsened motor function. Female rats exhibited a protective phenotype against such pathology86.
Notably, no existing studies have investigated the interaction between GC/GR signalling and mitochondrial dysfunction in the context of α-syn aggregation. However, there is an essential link between mitochondrial dysfunction and α-syn aggregation that can be theoretically extrapolated to GC/GR signalling, led exacerbation or progression of PD. Mitochondrial dysfunction and membrane permeability can promote α-syn oligomerization through release of ROS. ROS can damage α-syn and promote its aggregation in the mitochondria, where it inhibits complex 1, triggering a cyclical dysfunction87. Secondly, the mitochondrial membrane lipid cardiolipin interacts with mutant A53T α-syn to promote oligomerization and subsequently becomes sequestered within aggregates which causes further dysfunction in the mitochondria. Increased aggregation in A53T α-syn was associated with weakened respiration, loss of mitochondrial membrane potential, and elevated oxidative stress88. These factors catalyse early opening of mitochondrial membranes and apoptosis. However, whether GC/GR signalling–induced mitochondrial dysfunction drives α-syn aggregation through these processes remains to be confirmed in PD models.
α-syn exacerbated impaired neurogenesis and apoptosis
The role of α-syn in apoptosis alongside its influence on neurogenesis highlights its compounded contribution to neuronal vulnerability in PD and depression. The hippocampus serves as one of the two sites of adult neurogenesis in the brain. Deficit in adult neurogenesis is recognized as a pathological factor contributing to both PD and depression. BDNF is central to this process, as it not only supports neurogenesis via TrkB-mediated MAPK/ERK signalling, which supports proliferation, differentiation, and maturation of hippocampal neural stem cells into functional neurons89. BDNF also modulates apoptosis through the PI3K/Akt pathway. Akt in turn sequesters pro-apoptotic proteins such as BAD and BAX, thereby maintaining neuronal survival90. Thus, loss of BDNF signalling removes trophic support and lowers the threshold for apoptosis.
At a genetic level, the polymorphism Val66MET (G/G genotype) in BDNF was associated with a threefold risk of depression (p = 0.04) in patients with PD91. Furthermore, at a phenotypic level, loss of BDNF aggravated motor symptoms due to increased death of dopaminergic neurons in the SN. Serum BDNF was lower in depressed PD patients compared to non-depressed PD patients or controls92,93. The BDNF levels showed an inverse correlation with motor function (r = −0.54, p < 0.001) and PD severity (r = −0.45, p < 0.001)92. These findings underscore BDNF as a critical determinant of both depression susceptibility and PD progression.
Overexpression of human α-syn in 5-HT neurons of RN in mice led to decreased BDNF expression and reduced 5-HT neurotransmission in the forebrain resulting in a depressive phenotype. This phenotype was reversed by α-syn antisense oligonucleotide94. Yvan Y. and colleagues showed that α-syn overexpression inhibited PKC signalling, leading to GSK3β activation, ERK suppression, and consequent downregulation of BDNF with DA neuron degeneration95. Inhibiting the expression of α-syn ameliorated DA neurons degeneration through BDNF upregulation96. Treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with Parkinson’s Disease depression (PDD) raised BDNF to levels comparable with healthy controls and ameliorated motor symptoms97. Transgenic overexpression of α-syn in rats showed impaired neurogenesis and dendritogenesis of neuroblasts in the hippocampal dentate gyrus. Reduced neurogenesis corresponded with a deficiency in 5-HT neurotransmission, including downregulation of 5-HT, 5-HT 1B receptor and reduced serotonergic innervation in the DG/CA3 subfield. Additionally, α-syn overexpression led to loss of synapsin-1 and RIM3, essential proteins for vesicle release, which corresponded with an altered ultrastructural architecture of hippocampal synapses. All adverse changes to the hippocampus preceded motor function98. It is evident that α-syn plays a key role in the regulation of BDNF, a key player in neurogenesis and cell survival, and therefore may be working in concert with depression to exacerbate PD severity.
Serum and Glucocorticoid Receptor Kinase 1 (SGK1) is a downstream target of GR with a complex role in apoptosis regulation. Increased expression of SGK1 was associated with reduced hippocampal volume in a specific subset of depressed patients with history of childhood maltreatment99. Whereas Yeo S. et al. reported reduced levels of SGK1 were associated with increased phosphorylation and accumulation of α-syn in a murine model of MPTP-induced PD. SGK1 co-localized with α-syn in dopaminergic neurons and promoted cell death100. These findings position SGK1 as a potential mediator of apoptosis in the PD–depression axis, although its contradictory expression patterns currently limit a clinically meaningful conclusion. Future proteomic studies in patients with PD and comorbid depression may help clarify SGK1’s regulatory influence on α-syn and apoptotic pathways. In this context, it would also be valuable to investigate other apoptosis-related molecules with GREs recognized by GRs—such as BCL2—in in vitro and in vivo models of PDD. Finally, it is important to note that mitochondrial dysfunction, discussed previously, represents another pivotal apoptotic pathway converging on α-syn.
Taken together, depression in PD is best understood as a bidirectional interplay with α-syn pathology, where each process amplifies the other. This framework explains why depression may emerge years before motor symptoms (as a consequence of α-syn spread), while also acting as a driver of disease exacerbation through stress, inflammation, neurotransmitter dysregulation and apoptosis (Fig. 4).
Aggregation of α-syn worsens depressive symptoms in PD, while depression in turn promotes α-syn aggregation. Dysregulated HPA axis, dopaminergic dysfunction, mitochondrial impairment, loss of trophic support, and neuroinflammation converge to drive both α-syn accumulation and the molecular pathology of PDD. Collectively, these processes exacerbate PD, positioning α-syn as a convergent point between depression and PD. Figure created in BioRender. Phansupkar, A. (2025) https://BioRender.com/6btekql.
α-synuclein-associated networks in depression and Parkinson’s Disease: Insights from GWAS, expression data and functional enrichment tools
In this section, we employed a secondary analysis approach to uncover pathways and genes associated with aberrant α-syn in PD that are also shared with MDD and thus may potentially contribute to PDD or exacerbation of PD. The layout of the secondary analysis is described in Fig. 5. Firstly, the molecular interplay was deduced at a genomic level by performing a comprehensive search of the NHGRI-EBI GWAS Catalogue (https://www.ebi.ac.uk/gwas/) using the search terms “Parkinson’s Disease” or “Depression OR Major Depressive Disorders”. All catalogued studies were included except for those meeting the exclusion criteria i.e., (i) No SNCA polymorphisms reported in the significant associations of the PD cohort (ii) Patients with major confounding comorbidities or major neurological disorders (iii) Depression in distinct physiological conditions like post-partum or peri-natal periods for MDD cohorts (iv) Patients that are bipolar were not considered for MDD cohort. It is to be noted that all GWAS pertinent to PD (not MDD) were carefully selected based on significant associations of SNCA polymorphisms in the cohort. The genetic loci associated with PD and MDD overlapped. Finally, the common genetic loci were functionally annotated on Metascape (https://metascape.org/)101. Secondly, convergences in gene expression profiles of PD and MDD were studied using publicly available datasets on the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/). The search terms “Parkinson’s Disease” or “Depression” or “Major Depressive Disorders” were used and datasets were selected based on specific criteria: (i) For PD patients, SNCA was differentially expressed (ii) Datasets were sufficiently large, (iii) Gene expression profiling was performed on micro-array, (iv) Platform of case and control was same, (v) Healthy controls (HC) were available in same dataset, (vi) Diagnostic criteria for PD and MDD was clear, (vii) Samples were of the same type across all groups of comparisons and were sourced from human patients, and (viii) Patients with major confounding comorbidities or major neurological disorders. The Limma package under R software was used to obtain differentially expressed genes (DEGs) by comparing cases with HC under the Limma package. The threshold for significance was set at adjusted p-value <0.05 for MDD versus HC and P-value <0.05 for PD. DEGs from PD and MDD cohort were overlapped. Finally, functional and pathway annotation for the common DEGs was done using Metascape.
A Procurement and analysis of genomic datasets available on GWAS catalogue led to identification of 10 shared genetic loci associated with PD and MDD. All included PD datasets reported polymorphisms in SNCA so that the convergent genetic loci could be studied for potential link to α-syn pathology. B Procurement and analysis of transcriptomic datasets available on GEO omnibus led to identification of 57 shared differentially expressed genes (DEGs) associated with PD and MDD. The chosen dataset for PD differentially expressed SNCA so that the convergent genes could be studied for potential link to α-syn pathology. Figure created in BioRender. Phansupkar, A. (2025) https://BioRender.com/4rbsnjl.
PD patients with SNCA polymorphisms share genetic loci with MDD
In this series of secondary analysis on 20 GWAS catalogued in the GWAS Catalogue, we curated a list of 188 genetic loci associated with PD patients that reported SNPs in the SNCA gene. Simultaneously, we compiled a list of 1080 genetic loci associated with MDD from 48 GWAS (Supplementary Table S1). Both lists were intersected (Fig. 6A) and 10 genetic loci that were shared between the two diseases were identified in Table 1. The most remarkable shared genes were the kinase DYRK1A, HLA-DRB1 and HLA-DQA1. Their pertinence to PD, depression and α-syn pathology is detailed in Table 2. DYRK1A is known to phosphorylate α-syn, cause serotonergic and DA neuron death102,103. The latter HLA molecules present α-syn to T-cells and trigger inflammation104. This evidence supports the convergence of PD and depression at α-syn. Functional annotation placed HLA-DRB1 and HLA-DQA1 in the topmost significant “Vitamin D Receptor pathway” (Fig. 6B). Herein, we highlight the genomic susceptibility towards VDR pathway regulation in PD patients with SNCA polymorphisms, which can possibly underscore disease exacerbation. These results encourage the investigation of the pathway in the context of α-syn-led exacerbation of PD in the presence of comorbidities, especially PDD.
A Venn diagram demonstrating the overlap of genetic loci between PD patients with α-syn polymorphisms and patients with MDD. (B) Pathway annotation of the 10 common genes. Figure created in BioRender. Phansupkar, A. (2025) https://BioRender.com/0cv1z09.
Shared expression profile between PD and MDD patients displays pattern of increased immune response and apoptosis
Through this secondary transcriptomic analysis, we chose two large datasets (Supplementary Table S2) (GSE57475 for PD versus HC; GSE98793 for MDD versus HC) by performing a comprehensive search based on previously described selection criteria. Differential expression of α-syn in PD cohort was confirmed (p = 0.007). MDD versus HC yielded 2594 DEGs and PD versus HC yielded 386 DEGs (Fig. 7A). Of these, 57 were common between both groups as listed in Supplementary Table S3.
A Venn diagram demonstrating the overlap of DEGs between PD patients that differentially express α-syn and patients with MDD. B Pathway annotation of the 57 common DEGs. Figure created in BioRender. Phansupkar, A. (2025) https://BioRender.com/4cb408v.
Pathway annotation revealed “Innate immune response” and “Intrinsic apoptotic signalling pathways” as the most remarkable significant pathways (Fig. 7B). The logFC for genes significant to innate immunity and intrinsic apoptosis in PD and MDD (PD; MDD) generally ranged between 0.1 to 0.2. These included upregulation of MAP3K5 (FC = 0.14; 0.13) which plays a role in both processes. The upregulation of CARD8 (FC = 0.19; 0.25), GRB2 (FC = 0.2; 0.07), IRF2BPL (FC = 0.17; 0.06) and SP100 (FC = 0.09; 0.09) signifies a low-grade inflammation. Correspondingly, upregulation of TMEM127 (FC = 0.1; 0.14) may be indicative of cell death and possible neurodegeneration that is characteristic of the two diseases. The rise in logFC was remarkably subtle but is contextually important in cases of complex chronic/neurodegenerative conditions like PD and depression. Overall, this section offered a glimpse into the possible pathways and genes that may be exacerbating PD in presence of α-syn dysregulation and comorbidities.
Discussion
In this multi-omics analysis, we reported novel insights that are possibly associated with the role of α-syn as a convergent point between exacerbated PD and depression. Dysregulation of the VDR pathway, chronic activation of innate immunity and intrinsic apoptosis may contribute towards the neuroinflammation and neurodegeneration that exacerbate PD. Exploring these pathways in context of a genetic signature may have therapeutic value in inhibiting disease progression. To provide an integrative perspective, we compiled the key genes identified across GWAS and GEO datasets that were common to both PD and depression and mapped them to their potential links with α-syn pathology. This summary is presented in Table 2, which serves as a reference point for understanding how these genetic and transcriptomic factors converge to exacerbate disease processes. For instance, ASK1, a stress-activated apoptotic signalling kinase, mediates α-syn–induced phosphorylation and aggregation, while its suppression reduces nigrostriatal degeneration and even alleviates depressive behaviours, underscoring its dual relevance to neurodegeneration and mood regulation105,106. Similarly, SP100, an interferon-response gene, has been shown to bind α-syn and promote its aggregation under calcium-rich conditions; its upregulation in depressive states suggests that inflammatory signalling may amplify α-syn pathology while exacerbating mood symptoms107,108. From the immune-genetic perspective, HLA-DRB1/DQA1 alleles influence PD susceptibility and T-cell activation against α-syn epitopes, and their regulation via vitamin D receptor elements links neuroinflammation to broader metabolic and environmental factors109,110,111. Vitamin D receptor (VDR) pathway is well-known for its neuroprotective role in various neurodegenerative diseases, including PD and MDD. Evidence has shown that Vitamin D and VDRs are highly expressed in the brain where they exert beneficial effects. This includes upregulation of trophic factors like BDNF, immunomodulation by lowering the levels of TNF-α and NFκB, improving dopaminergic activity and reducing oxidative stress112. Unsurprisingly, Vitamin D deficiency is common amongst PD patients113. Finally, DYRK1A, a kinase that directly phosphorylates α-syn, contributes to dopaminergic and serotonergic neuronal vulnerability, bridging motor and affective symptoms102,103. Collectively, these examples illustrate how modest transcriptomic and genetic alterations converge mechanistically on apoptosis, inflammation, and α-syn–mediated neurotoxicity to exacerbate PD in the context of depression.
Importantly, the fold changes observed in our secondary transcriptomic analyses were modest, yet such values are meaningful. Bulk RNA-seq of peripheral blood mononuclear cells reflects a heterogenous cell population. This dilutes subset-specific expression changes, thereby reflecting small logFC values for DEGs that may be strongly altered in immune subsets. Differences in tissue type also influences the amplitude of expression changes, with peripheral blood typically yielding smaller effect sizes compared to post-mortem brain tissues or CSF. Importantly, the functional interpretation of these findings lies not in fold change magnitude alone, but in the mechanistic roles of the identified genes in apoptosis, inflammation, and α-syn biology (Table 2). In addition, within polygenic disorders such as PD and MDD, small but consistent transcriptomic alterations may be more informative than large, isolated changes.
The short series of secondary analyses is not without limitations. There is no definitive uniformity in symptom severity of the patients in the cohort, furthermore, the status of disease exacerbation is unknown which makes it imperative for these insights to be validated in future cohorts/in-vivo/in-vitro models to solidify the role of α-syn as a convergent point between exacerbated PD and depression. The ethnicities of patient cohort are diverse and non-uniform but that contributes to the practical robustness of the data. Lastly, it is important to acknowledge that studying the genome and transcriptome of patients does not override the need for translational proof. Indeed, supplementation of proteomic data would strengthen the outcome of these secondary analyses.
Therapeutic implications
Depression prevalence among patients with PD can range from 2.7% to more than 90% of the patients114. About 63% of depressed patients are prescribed SSRIs and 7% are prescribed tricyclic antidepressants115. A systematic review and metanalysis of six randomized controlled trials (RCTs) showed that the efficacy of this treatment approach is not statistically significant116. Evidently, patients with PD and depression form a sizeable portion of the PD patient pool, making it crucial to factor in such complexity in the medical treatment plan.
In this review we highlighted several interactions between the pathological hallmark of PD (LBs) and dysregulated pathways of depression in PD (Fig. 8). Considering all elucidated evidence, we advocate the clinical practice of differential diagnosis using α-syn along with standardized scales to measure depression. This will support clinicians to categorize patients with different endophenotype and ultimately suggest precise solutions for the patients based on their gene expression profiles. At the same time, targeting α-syn can be included in the treatment plan. Unfortunately, immunotherapy approaches targeting α-syn have been unsuccessful in showing clinical improvement117. This highlights the translational gap between promising preclinical data and clinical efficacy. One potential strategy to bridge this gap is initiating such approaches in concert with established antidepressant regimens or adjunct therapies tailored to PD endophenotypes. Antidepressants have been successful in improving NMS in PD patients118. Combining α-syn–targeted interventions with serotonergic modulation, for example, may enhance neuroprotection, improve NMS, and promote neuro-rescue. In this context, omics-guided patient stratification could help identify individuals most likely to benefit from combinatorial regimens, thereby aligning molecular insights with precision medicine strategies in PD and depression. We believe the mechanistic pathways discussed in this review can potentially facilitate patient stratification. But that first requires ample validation in patient cohorts.
A Depression along-with α-syn may bridge the gap between early diagnosis and clinical PD. The sequential spread of aggregated α-syn/ Lewy bodies in the prodromal stage of PD disrupts neurotransmitter systems. Loss of neurotransmitter transporters contributes to depression, a prevalent feature of prodromal disease stage that may precede clinical diagnosis by a decade. Using α-syn along with depression as a biomarker may facilitate diagnosis of PD before major loss of motor neurons. B α-syn accumulation interacts with multiple pathological processes—HPA axis dysregulation, mitochondrial impairment, loss of trophic support, apoptosis, oxidative stress and neuroinflammation—creating a bidirectional loop between PD and depression. This interplay culminates in Parkinson’s Disease depression (PDD), driving exacerbation and progression of PD. C Multi-omics approach was used to identify novel convergent pathways/gene between PD and depression positioning α-syn at the centre. Genome-wide association studies (GWAS) focusing on SNCA polymorphisms in PD were overlapped with depression genetic loci. In parallel, transcriptomic datasets comparing PD and MDD patients to healthy controls were analysed for differentially expressed genes. Shared loci/genes were enriched for apoptosis, innate immune response and vitamin D receptor pathway. Figure created in BioRender. Phansupkar, A. (2025) https://BioRender.com/kt8tr1f.
Another application is hand in hand usage of α-syn and depression in screening and/or diagnosis of PD in the prodromal stage (Fig. 8). The development of accessible liquid biopsies such as blood, serum, plasma and saliva is crucial for such strategies to take effect. Prospective studies must explore the reliability of liquid biopsies in prediction of disease stage using the previously discussed molecular markers of the brain.
Conclusion
In conclusion, we provided a comprehensive view of interactions between the molecular pathophysiology associated with PD and its prevalent comorbidity - depression, with a focus on α-syn as a convergent point. Beyond summarizing existing evidence, we also contribute new insights by identifying genetic signatures that link depression to α-syn pathology. These findings may help bridge the persistent gap between PD pathophysiology and early diagnosis.
Data availability
This work included secondary analyses from publicly available datasets. The datasets used were procured from the NCBI Gene Expression Omnibus (GEO) and the NHGRI-EBI GWAS Catalog. GEO dataset accession numbers and GWAS studies are listed and referenced in the supplementary information. No new datasets were generated or deposited.
References
Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet 386, 896–912 (2015).
Stoker, T. B. & Greenland, J. C. Parkinson’s disease: pathogenesis and clinical aspects [internet]. (2018).
Lees, A. An essay on the shaking palsy. Brain 140, 843–848 (2017).
Koeglsperger, T. et al. Neuropathology of incidental Lewy body & prodromal Parkinson’s disease. Mol. Neurodegen. 18, 32 (2023).
Halliday, G. M. & Stevens, C. H. Glia: initiators and progressors of pathology in Parkinson’s disease. Mov. Disord. 26, 6–17 (2011).
Calabresi, P. et al. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 14, 176 (2023).
Durcan, R. et al. Prevalence and duration of non-motor symptoms in prodromal Parkinson’s disease. Eur. J. Neurol. 26, 979–985 (2019).
Khedr, E. M., Abdelrahman, A. A., Elserogy, Y., Zaki, A. F. & Gamea, A. Depression and anxiety among patients with Parkinson’s disease: frequency, risk factors, and impact on quality of life. Egypt. J. Neurol., Psychiatry Neurosurg. 56, 1–9 (2020).
Braak, H., Ghebremedhin, E., Rüb, U., Bratzke, H. & Del Tredici, K. Stages in the development of Parkinson’s disease-related pathology. Cell tissue Res. 318, 121–134 (2004).
Meade, R. M., Fairlie, D. P. & Mason, J. M. Alpha-synuclein structure and Parkinson’s disease–lessons and emerging principles. Mol. Neurodegen. 14, 1–14 (2019).
Park, J. et al. Dexamethasone induces the expression of LRRK2 and a-synuclein, two genes that when mutated cause Parkinson is disease in an autosomal dominant manner. Biochem. Mol. Biol. Rep. 46 (2013).
Nakos Bimpos, M. et al. Alpha-synuclein-induced stress sensitivity renders the Parkinson’s disease brain susceptible to neurodegeneration. Acta Neuropathol. Commun. 12, 100 (2024).
Burtscher, J. et al. Chronic corticosterone aggravates behavioral and neuronal symptomatology in a mouse model of alpha-synuclein pathology. Neurobiol. aging 83, 11–20 (2019).
Jeannotte, A. M. & Sidhu, A. Regulation of the norepinephrine transporter by α-synuclein-mediated interactions with microtubules. Eur. J. Neurosci. 26, 1509–1520 (2007).
Pålhagen, S., Carlsson, M., Curman, E., Wålinder, J. & Granérus, A. K. Depressive illness in Parkinson’s disease–indication of a more advanced and widespread neurodegenerative process? Acta Neurol. Scand. 117, 295–304 (2008).
Bungeroth, M. et al. Differential aggregation properties of alpha-synuclein isoforms. Neurobiol. aging 35, 1913–1919 (2014).
Nielsen, M. S., Vorum, H., Lindersson, E. & Jensen, P. H. Ca2+ binding to α-synuclein regulates ligand binding and oligomerization. J. Biol. Chem. 276, 22680–22684 (2001).
Burré, J. et al. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663–1667 (2010).
Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18, 101–113 (2017).
Bartels, T., Choi, J. G. & Selkoe, D. J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477, 107–110 (2011).
Tenreiro, S., Eckermann, K. & Outeiro, T. F. Protein phosphorylation in neurodegeneration: friend or foe? Front. Mol. Neurosci. 7, 42 (2014).
Fusco, G. et al. Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour. Nat. Commun. 5, 3827 (2014).
Zafar, F. et al. Genetic fine-mapping of the Iowan SNCA gene triplication in a patient with Parkinson’s disease. npj Parkinson’s. Dis. 4, 18 (2018).
Ahn, T.-B. et al. α-Synuclein gene duplication is present in sporadic Parkinson disease. Neurology 70, 43–49 (2008).
Forloni, G. Alpha synuclein: neurodegeneration and inflammation. Int. J. Mol. Sci. 24, 5914 (2023).
Fernandes, M. et al. Frequency of non-motor symptoms in Parkinson’s patients with motor fluctuations. Front. Neurol. 12, 678373 (2021).
Du, T. et al. Hippocampal alpha-synuclein mediates depressive-like behaviors. Brain Behav. Immun. 95, 226–237 (2021).
Rotter, A. et al. Alpha-synuclein RNA expression is increased in major depression. Int. J. Mol. Sci. 20, 2029 (2019).
Ishiguro, M. et al. Increased serum levels of α-synuclein in patients with major depressive disorder. Am. J. Geriatr. Psychiatry 27, 280–286 (2019).
Bruno, D. et al. CSF α-synuclein correlates with CSF neurogranin in late-life depression. Int. J. Neurosci. 131, 357–361 (2021).
Hassamal, S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Front. Psychiatry 14, 1130989 (2023).
Knezevic, E., Nenic, K., Milanovic, V. & Knezevic, N. N. The role of Cortisol in chronic stress, neurodegenerative diseases, and psychological disorders. Cells 12, 2726 (2023).
Sugama, S. et al. Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: possible role of chronic stress in the onset of Parkinson’s disease. Brain Behav. Immun. 51, 39–46 (2016).
DeMorrow, S. Vol. 19 986 (MDPI, 2018).
Litwack, G. Chapter 15 - Polypeptide Hormones. Second edn, 475–516 (Elsevier, 2022).
Alhaj, H. A., Massey, A. E. & McAllister-Williams, R. H. Effects of cortisol on the laterality of the neural correlates of episodic memory. J. Psychiatr. Res. 42, 971–981 (2008).
Alhaj, H. A., Massey, A. E. & McAllister-Williams, R. H. A study of the neural correlates of episodic memory and HPA axis status in drug-free depressed patients and healthy controls. J. Psychiatr. Res. 41, 295–304 (2007).
Koning, A.-S. C., Buurstede, J. C., van Weert, L. T. & Meijer, O. C. Glucocorticoid and mineralocorticoid receptors in the brain: a transcriptional perspective. J. Endocr. Soc. 3, 1917–1930 (2019).
Juszczak, G. R. & Stankiewicz, A. M. Glucocorticoids, genes and brain function. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 82, 136–168 (2018).
Jenkins, S. I. et al. Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy. ACS Chem. Neurosci. 5, 51–63 (2014).
Franchimont, D. et al. Tumor necrosis factor α decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor. J. Clin. Endocrinol. Metab. 84, 2834–2839 (1999).
Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A. & Karin, M. Immunosuppression by glucocorticoids: inhibition of NF-κB activity through induction of IκB synthesis. Science 270, 286–290 (1995).
Bushell, K. N. et al. LITAF mediation of increased TNF-α secretion from inflamed colonic lamina propria macrophages. PloS One 6, e25849 (2011).
Guidotti, G. et al. Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuropsychopharmacology 38, 616–627 (2013).
Sahu, M. K., Dubey, R. K., Chandrakar, A., Kumar, M. & Kumar, M. A systematic review and meta-analysis of serum and plasma cortisol levels in depressed patients versus control. Indian J. Psychiatry 64, 440–448 (2022).
Kumamaru, E., Numakawa, T., Adachi, N. & Kunugi, H. Glucocorticoid suppresses BDNF-stimulated MAPK/ERK pathway via inhibiting interaction of Shp2 with TrkB. FEBS Lett. 585, 3224–3228 (2011).
You, J.-M. et al. Mechanism of glucocorticoid-induced oxidative stress in rat hippocampal slice cultures. Can. J. Physiol. Pharmacol. 87, 440–447 (2009).
Håglin, L. & Bäckman, L. Covariation between plasma phosphate and daytime cortisol in early Parkinson’s disease. Brain Behav. 6, e00556 (2016).
Kostić, V. S. et al. Dexamethasone suppression test in patients with Parkinson’s disease. Mov. Disord.: J. Mov. Disord. Soc. 5, 23–26 (1990).
Rabey, J. M., Scharf, M., Oberman, Z., Zohar, M. & Graff, E. Cortisol, ACTH, and beta-endorphin after dexamethasone administration in Parkinson’s dementia. Biol. Psychiatry 27, 581–591 (1990).
Říha, P., Brabenec, L., Mareček, R., Rektor, I. & Rektorová, I. The reduction of hippocampal volume in Parkinson’s disease. J. Neural Transm. 129, 575–580 (2022).
Huang, P. et al. Abnormal amygdala function in Parkinson’s disease patients and its relationship to depression. J. Affect. Disord. 183, 263–268 (2015).
van Mierlo, T. J., Chung, C., Foncke, E. M., Berendse, H. W. & van den Heuvel, O. A. Depressive symptoms in Parkinson’s disease are related to decreased hippocampus and amygdala volume. Mov. Disord. 30, 245–252 (2015).
Jeong, G. R. & Lee, B. D. Pathological functions of LRRK2 in Parkinson’s disease. Cells 9, 2565 (2020).
Park, J.-M. et al. Dexamethasone induces the expression of LRRK2 and α-synuclein, two genes that when mutated cause Parkinson’s disease in an autosomal dominant manner. BMB Rep. 46, 454 (2013).
Lin, X. et al. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant α-synuclein. Neuron 64, 807–827 (2009).
Villar-Conde, S. et al. The human hippocampus in Parkinson’s disease: an integrative stereological and proteomic study. J. Parkinson’s. Dis. 11, 1345–1365 (2021).
Wassouf, Z. et al. Distinct stress response and altered striatal transcriptome in alpha-synuclein overexpressing mice. Front. Neurosci. 12, 1033 (2019).
Azmitia, E. & Whitaker-Azmitia, P. Awakening the sleeping giant: anatomy and plasticity of the brain serotonergic system. J. Clin. Psychiatry 52, 4–16 (1991).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).
Wilson, H. et al. Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study. Lancet Neurol. 18, 748–759 (2019).
Halliday, G., Blumbergs, P., Cotton, R., Blessing, W. & Geffen, L. Loss of brainstem serotonin-and substance P-containing neurons in Parkinson’s disease. Brain Res. 510, 104–107 (1990).
Albin, R. L. et al. Spared caudal brainstem SERT binding in early Parkinson’s disease. J. Cereb. Blood Flow. Metab. 28, 441–444 (2008).
Bortolozzi, A. et al. Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like. phenotype. Rescue by oligonucleotide therapy, (2021).
Mizuno, Y., Ashok, A. H., Bhat, B. B., Jauhar, S. & Howes, O. D. Dopamine in major depressive disorder: A systematic review and meta-analysis of in vivo imaging studies. J. Psychopharmacol. 37, 1058–1069 (2023).
Isovich, E., Mijnster, M. J., Flügge, G. & Fuchs, E. Chronic psychosocial stress reduces the density of dopamine transporters. Eur. J. Neurosci. 12, 1071–1078 (2000).
Dalvi-Garcia, F., Fonseca, L. L., Vasconcelos, A. T. R., Hedin-Pereira, C. & Voit, E. O. A model of dopamine and serotonin-kynurenine metabolism in cortisolemia: Implications for depression. PLoS Comput. Biol. 17, e1008956 (2021).
Agid, Y. Biochemistry of neurotransmitters in Parkinson’s disease. Mov. Disord. 2, 166–230 (1987).
Hurst, J. H., LeWitt, P. A., Burns, R. S., Foster, N. L. & Lovenberg, W. CSF dopamine–hydroxylase activity in Parkinson’s disease. Neurology 35, 565–565 (1985).
Remy, P., Doder, M., Lees, A., Turjanski, N. & Brooks, D. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128, 1314–1322 (2005).
Richard, I. et al. A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology 78, 1229–1236 (2012).
Bonuccelli, U. et al. A non-comparative assessment of tolerability and efficacy of duloxetine in the treatment of depressed patients with Parkinson’s disease. Expert Opin. Pharmacother. 13, 2269–2280 (2012).
Lehrer, S. & Rheinstein, P. H. α-synuclein enfolds tyrosine hydroxylase and dopamine ß-hydroxylase, potentially reducing dopamine and norepinephrine synthesis. J. Proteins Proteom. 13, 109–115 (2022).
Jeannotte, A. M., McCarthy, J. G., Redei, E. E. & Sidhu, A. Desipramine modulation of α-, γ-synuclein, and the norepinephrine transporter in an animal model of depression. Neuropsychopharmacology 34, 987–998 (2009).
Grotemeyer, A., McFleder, R. L., Wu, J., Wischhusen, J. & Ip, C. W. Neuroinflammation in Parkinson’s disease-putative pathomechanisms and targets for disease-modification. Front. Immunol. 13, 878771 (2022).
Troubat, R. et al. Neuroinflammation and depression: A review. Eur. J. Neurosci. 53, 151–171 (2021).
Latham, A. S., Rocha, S. M., McDermott, C. P., Reigan, P. & Tjalkens, R. B. Neuroprotective efficacy of the glucocorticoid receptor modulator PT150 in the rotenone mouse model of Parkinsons disease. bioRxiv, 2024.2004. 2012.589261 (2024).
Maatouk, L. et al. TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons. Nat. Commun. 9, 2450 (2018).
Ren, C. et al. Depression induced by chronic unpredictable mild stress increases susceptibility to Parkinson’s disease in mice via neuroinflammation mediated by P2X7 receptor. ACS Chem. Neurosci. 12, 1262–1272 (2021).
Solini, A. et al. P2X7 receptor/NLRP3 inflammasome complex and α-synuclein in peripheral blood mononuclear cells: a prospective study in neo-diagnosed, treatment-naïve Parkinson’s disease. Eur. J. Neurol. 28, 2648–2656 (2021).
Wilkaniec, A. et al. P2X7 receptor is involved in mitochondrial dysfunction induced by extracellular alpha synuclein in neuroblastoma SH-SY5Y cells. Int. J. Mol. Sci. 21, 3959 (2020).
Valera, E., Ubhi, K., Mante, M., Rockenstein, E. & Masliah, E. Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia 62, 317–337 (2014).
Hao, Y., Shabanpoor, A. & Metz, G. A. Stress and corticosterone alter synaptic plasticity in a rat model of Parkinson’s disease. Neurosci. Lett. 651, 79–87 (2017).
Somayaji, M. et al. A dual role for α-synuclein in facilitation and depression of dopamine release from substantia nigra neurons in vivo. Proc. Natl. Acad. Sci. 117, 32701–32710 (2020).
Claros, S. et al. Impact of glucocorticoid on a cellular model of Parkinson’s disease: oxidative stress and mitochondrial function. Brain Sci. 11, 1106 (2021).
Grigoruţă, M., Martínez-Martínez, A., Dagda, R. Y. & Dagda, R. K. Psychological stress phenocopies brain mitochondrial dysfunction and motor deficits as observed in a parkinsonian rat model. Mol. Neurobiol. 57, 1781–1798 (2020).
Reeve, A. et al. Aggregated α-synuclein and complex I deficiency: exploration of their relationship in differentiated neurons. Cell Death Dis. 6, e1820–e1820 (2015).
Choi, M. L. et al. Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity. Nat. Neurosci. 25, 1134–1148 (2022).
Wei, Z., Liao, J., Qi, F., Meng, Z. & Pan, S. Evidence for the contribution of BDNF-TrkB signal strength in neurogenesis: An organotypic study. Neurosci. Lett. 606, 48–52 (2015).
Almeida, R. et al. Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ. 12, 1329–1343 (2005).
Cagni, F. C. et al. Association of BDNF Val66MET polymorphism with Parkinson’s disease and depression and anxiety symptoms. J. neuropsychiatry Clin. Neurosci. 29, 142–147 (2017).
Huang, Y., Huang, C., Zhang, Q., Wu, W. & Sun, J. Serum BDNF discriminates Parkinson’s disease patients with depression from without depression and reflect motor severity and gender differences. J. Neurol. 268, 1411–1418 (2021).
Wang, Y. et al. Association of low serum BDNF with depression in patients with Parkinson’s disease. Parkinson. Relat. Disord. 41, 73–78 (2017).
Miquel-Rio, L. et al. Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy. Transl. Psychiatry 12, 79 (2022).
Yuan, Y. et al. Overexpression of α-synuclein down-regulates BDNF expression. Cell. Mol. Neurobiol. 30, 939–946 (2010).
Cao, Q. et al. Suppression of abnormal α-synuclein expression by activation of BDNF transcription ameliorates Parkinson’s disease-like pathology. Mol. Ther. -Nucleic Acids 29, 1–15 (2022).
Ricci, V. et al. P01-479-Antidepressant treatment restores brain-derived neurotrophic factor (BDNF) serum levels and ameliorates motor function in parkinson’s disease patients. Eur. Psychiatry 26, 483 (2011).
Kohl, Z. et al. Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson’s disease. Neurobiol. Dis. 85, 206–217 (2016).
Mazurka, R. et al. Relation of hippocampal volume and SGK1 gene expression to treatment remission in major depression is moderated by childhood maltreatment: a CAN-BIND-1 report. Eur. Neuropsychopharmacol. 78, 71–80 (2024).
Yeo, S. et al. Decreased expression of serum-and glucocorticoid-inducible kinase 1 (SGK1) promotes alpha-synuclein increase related with down-regulation of dopaminergic cell in the Substantia Nigra of chronic MPTP-induced Parkinsonism mice and in SH-SY5Y cells. Gene 661, 189–195 (2018).
Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).
Yong, Y. et al. Dyrk1a Phosphorylation of α-Synuclein Mediating Apoptosis of Dopaminergic Neurons in Parkinson’s Disease. Parkinson’s. Dis. 2023, 8848642 (2023).
London, J. et al. Overexpression of the DYRK1A gene (dual-specificity tyrosine phosphorylation-regulated kinase 1A) induces alterations of the serotoninergic and dopaminergic processing in murine brain tissues. Mol. Neurobiol. 55, 3822–3831 (2018).
Garretti, F. et al. Interaction of an α-synuclein epitope with HLA-DRB1∗ 15: 01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease. Neuron 111, 3397–3413. e3395 (2023).
Zhang, J. et al. Apoptosis signal regulating kinase 1 deletion mitigates α-synuclein pre-formed fibril propagation in mice. Neurobiol. aging 85, 49–57 (2020).
Lan, T. et al. Agomelatine rescues lipopolysaccharide-induced neural injury and depression-like behaviors via suppression of the Gαi-2-PKA-ASK1 signaling pathway. J. Neuroinflamm. 19, 117 (2022).
Toleikis, Z. et al. Interactions between s100a9 and alpha-synuclein: insight from NMR spectroscopy. Int. J. Mol. Sci. 23, 6781 (2022).
Lorenz, D. R., Misra, V. & Gabuzda, D. Transcriptomic analysis of monocytes from HIV-positive men on antiretroviral therapy reveals effects of tobacco smoking on interferon and stress response systems associated with depressive symptoms. Hum. Genomics 13, 59 (2019).
Kraus, A. U., Penna-Martinez, M., Shoghi, F., Meyer, G. & Badenhoop, K. Monocytic cytokines in autoimmune polyglandular syndrome type 2 are modulated by vitamin D and HLA-DQ. Front. Immunol. 11, 583709 (2020).
Yu, E. et al. Fine mapping of the HLA locus in Parkinson’s disease in Europeans. npj Parkinson’s. Dis. 7, 84 (2021).
Pandi, S. et al. Association of HLA–DRB1, DQA1 and DQB1 alleles and haplotype in Parkinson’s disease from South India. Neurosci. Lett. 765, 136296 (2021).
Al-Kuraishy, H. M. et al. Does vitamin D protect or treat Parkinson’s disease? A narrative review. Naunyn-Schmiedeberg’s. Arch. Pharmacol. 397, 33–40 (2024).
Detopoulou, P. et al. Vitamin D in Parkinson’s disease: A systematic review of randomized controlled trials. Clin. Nutr. Open Sci. 52, 1–13 (2023).
Reijnders, J. S., Ehrt, U., Weber, W. E., Aarsland, D. & Leentjens, A. F. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov. Disord. 23, 183–189 (2008).
Chen, P. et al. Antidepressant treatment of veterans with Parkinson’s disease and depression: analysis of a national sample. J. Geriatr. psychiatry Neurol. 20, 161–165 (2007).
Skapinakis, P. et al. Efficacy and acceptability of selective serotonin reuptake inhibitors for the treatment of depression in Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials. BMC Neurol. 10, 1–11 (2010).
Zhan, X., Wen, G., Wu, X. & Li, J.-Y. Immunization targeting diseased proteins in synucleinopathy and tauopathy: insights from clinical trials. Transl. Neurodegen. 14, 33 (2025).
Pena, E. et al. Antidepressants in Parkinson’s disease. Recommendations by the movement disorder study group of the Neurological Association of Madrid. Neurol.ía (Engl. Ed.) 33, 395–402 (2018).
Lee, K.-W. et al. Apoptosis signal-regulating kinase 1 modulates the phenotype of α-synuclein transgenic mice. Neurobiol. aging 36, 519–526 (2015).
Ilješ, A. P., Plesničar, B. K. & Dolžan, V. Associations of NLRP3 and CARD8 gene polymorphisms with alcohol dependence and commonly related psychiatric disorders: a preliminary study. Arch. Ind. Hyg. Toxicol. 72, 191 (2021).
Qi, L. F. R. et al. Ginsenoside Rg3 restores mitochondrial Cardiolipin homeostasis via GRB2 to prevent Parkinson’s disease. Adv. Sci. 11, 2403058 (2024).
Zeng, Y. et al. Identification of potential biomarkers and pathways related to major depressive disorder by integrated bioinformatic analysis and experimental validation. Asian Pac. J. Trop. Biomed. 15, 200–209 (2025).
Zhang, J. et al. Identification of key genes and diagnostic model associated with circadian rhythms and Parkinson’s disease by bioinformatics analysis. Front. Aging Neurosci. 16, 1458476 (2024).
Heath, J. E. et al. Widespread distribution of reticulon-3 in various neurodegenerative diseases. Neuropathology 30, 574–579 (2010).
Li, C. et al. Mutation analysis of TMEM family members for early-onset Parkinson’s disease in Chinese population. Neurobiol. Aging 101, 299.e291–299.e296 (2021).
Manjur, A. K., Lempiäinen, J. K., Malinen, M., Palvimo, J. J. & Niskanen, E. A. IRF2BP2 modulates the crosstalk between glucocorticoid and TNF signaling. J. Steroid Biochem. Mol. Biol. 192, 105382 (2019).
Cen, L. et al. Association of DYRK1A polymorphisms with sporadic Parkinson’s disease in Chinese Han population. Neurosci. Lett. 632, 39–43 (2016).
Barallobre, M.-J. et al. DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson’s disease. Cell Death Dis. 5, e1289–e1289 (2014).
Ozono, T. et al. Extracellular transportation of α-synuclein by HLA class II molecules. Biochem. Biophys. Res. Commun. 644, 25–33 (2023).
Cheng, B. et al. Associations of classical HLA alleles with depression and anxiety. Hla 103, e15173 (2024).
Foley, É. M., Parkinson, J. T., Mitchell, R. E., Turner, L. & Khandaker, G. M. Peripheral blood cellular immunophenotype in depression: a systematic review and meta-analysis. Mol. Psychiatry 28, 1004–1019 (2023).
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RH is funded by the University of Sharjah (grant no: 24010902153).
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A.M.Y.: Conceptualization and preparation of original draft. B.Y.: Conceptualization, supervision, reviewing and editing. H.A.A.: Conceptualization, supervision, reviewing & editing. R.H.: Conceptualization, supervision, reviewing & editing.
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Yusuf, A.M., Ilce, B.Y., Alhaj, H.A. et al. α-synuclein in Parkinson’s disease: a central point of convergence with depression. npj Parkinsons Dis. 11, 329 (2025). https://doi.org/10.1038/s41531-025-01167-w
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DOI: https://doi.org/10.1038/s41531-025-01167-w
