Serotonergic Dysfunction in Parkinson's Disease

Parkinson’s disease has traditionally been characterised by degeneration of dopaminergic neurons in the substantia nigra, giving rise to its cardinal motor symptoms. However, a growing body of evidence implicates early and progressive dysfunction of the serotonergic system in the brainstem raphe nuclei. Serotonergic neurons exhibit alpha-synuclein aggregates and axonal pathology that precede or accompany dopaminergic loss, contributing to non-motor features such as depression, anxiety, fatigue and cognitive impairment. Neuroimaging and post-mortem studies reveal reduced serotonin transporter availability, altered receptor profiles and diminished serotonin metabolite levels in cerebrospinal fluid. Animal and cellular models demonstrate that disrupted axonal transport, synaptic release deficits and neuroinflammatory processes amplify serotonergic vulnerability. These changes interact with dopaminergic circuits, shaping network reorganisation and symptom heterogeneity. Understanding serotonergic alterations offers opportunities for early biomarkers, refined clinical stratification and novel therapies targeting serotonin receptors, transporters or upstream regulators of alpha-synuclein pathology.

Research from Nature Portfolio

Recent studies have harnessed patient-specific brain modelling to map the spatial distribution of multiple neurotransmitter receptors, including those for serotonin, against patterns of grey matter atrophy and functional dysregulation. This integrative approach reveals that serotonergic receptor architecture modulates regional vulnerability, correlating with both motor and non-motor symptom axes. Variability in receptor-mediated mechanisms across individuals helps explain differences in progression rates and clinical phenotypes, underscoring distinct co-existing processes that shape neural reorganisation in Parkinson’s disease.

Serotonergic Dysfunction in Parkinson's Disease publication trend

The graph below shows the total number of articles in serotonergic dysfunction in parkinson's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Serotonergic system: Network of neurons that synthesise, release and regulate serotonin as a neurotransmitter in the central nervous system.

Alpha-synuclein: Presynaptic protein prone to misfolding and aggregation, forming Lewy inclusions that disrupt neuronal function in Parkinson’s disease.

Serotonin transporter (SERT): Membrane protein responsible for the reuptake of serotonin from the synaptic cleft, regulating neurotransmitter clearance.

Raphe nuclei: Collection of serotonin-producing nuclei in the brainstem that project widely to cortical and subcortical regions.

References

1. Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson’s disease. Nature Communications (2023).
2. The Role of α-Synuclein in the Regulation of Serotonin System: Physiological and Pathological Features. Biomedicines (2023).
3. Early Degeneration of Both Dopaminergic and Serotonergic Axons – A Common Mechanism in Parkinson’s Disease. Frontiers in Cellular Neuroscience (2016).
4. Serotonergic Dysfunction in Parkinson′s Disease and Its Relevance to Disability. The Scientific World JOURNAL (2011).
5. Serotonin Impairment in CSF of PD Patients, without an Apparent Clinical Counterpart. PLOS ONE (2014).
6. Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy. Translational Psychiatry (2022).
7. High-resolution PET imaging reveals subtle impairment of the serotonin transporter in an early non-depressed Parkinson’s disease cohort. European Journal of Nuclear Medicine and Molecular Imaging (2020).
8. An Early Disturbance in Serotonergic Neurotransmission Contributes to the Onset of Parkinsonian Phenotypes in Drosophila melanogaster. Cells (2022).