Table 2 Genes associated with PD and depression identified from secondary analyses: Functional relevance and potential links to α-synuclein pathology

MAP3K/ASK1

The ASK1/MKK/JNK signalling pathway regulates apoptosis.

Overexpression of α-syn activated ASK1¹¹⁹.

Deletion of ASK1 resulted in decreased phosphorylation, aggregation and propagation of α-syn, reduced nigrostriatal pathway degeneration¹⁰⁵.

Suppression of ASK1 rescued rats from depressive behaviours¹⁰⁶.

α-syn in pathological conditions uses ASK1 as a mediator to exert neurodegenerative effects. ASK1 in turn may be supportive of pathological changes to α-syn under stress.

CARD8

Inflammasome gene that promotes pyroptosis and inflammation upon activation.

N/A

Functional inactivation of CARD8 by polymorphism (rs2043211) was associated with higher anxiety scores amongst abstinent alcohol-dependent participants¹²⁰.

There is no direct link between α-syn and CARD8 yet. It can be hypothesized that cell-stress induced by α-syn aggregates may be sensed by CARD8, triggering cell death and inflammation.

GRB2

GRB2 is an adaptor protein that notably mediates MAPK pathways, hence crucial for cell survival and cell proliferation (particularly important for immune cell response).

Cardiolipin response was augmented by virtue of the GRB2-TRKA-EVI1-CRLS1 axis, resulting in improved mitophagy, unfolded protein response and motor symptoms in PD¹²¹.

GRB2 identified as a “hub gene” from secondary analysis on three transcriptomic datasets of patients with depression. It was upregulated in hippocampi of rats with simulated depression¹²².

There is no direct link between α-syn and GRB2 yet. But, it can be hypothesized that α-syn aggregates upsets the mediatory role of GRB2 by interfering with downstream signalling pathways that determine cell survival and inflammation.

RTN3

Impairs clearance of cytosolic protein, promotes ER stress and apoptosis.

RTN3 was upregulated in transcriptome of PD patients¹²³. It was also found in Lewy Bodies in post-mortem tissues¹²⁴.

N/A

RTN3 appears to work in concert with α-syn pathology to prevent clearing up of accumulated protein and promote neurodegeneration.

SP100

Interferon response gene upregulated by interferons.

SP100 can bind to N-terminus of α-syn and leads to its aggregation in presence of Calcium¹⁰⁷.

Upregulation of SP100 was associated with depressive symptoms in HIV+ men¹⁰⁸.

The interaction between SP100 and α-syn needs to be studied mechanistically under pathological conditions. Based on current literature it can by hypothesized that SP100 may promote aggregation of α-syn under pathological imbalances. SP100 may further contribute to disease exacerbation by supporting inflammation and α-syn aggregation.

TMEM127

Regulator of mTORC.

mTORC controls autophagy and cell survival.

Mutations in members of TMEM gene family were associated with early-onset PD¹²⁵.

N/A

Disruptions to autophagy may lead to accumulation of α-syn.

IRF2BPL

Regulates inflammatory responses in various cell types.

N/A

Coactivator of GR and NFκB¹²⁶.

IRF2BPL coactivates GR. GR transactivates SNCA. NFκB led neuroinflammation can lead to accumulation of α-syn.

DYRK1A

Kinase activity implicated in multiple neurodegenerative diseases.

DYRK1A phosphorylates α-syn.Silencing DYRK1A rescued DA neurons from apoptosis and lowered p-α-syn¹⁰².

Genetic variation in DYRK1A was associated to increased risk of PD¹²⁷.

DYRK1A promoted survival of DA neurons after MPTP¹²⁸.

DYRK1A overexpression led to serotonin and dopamine deficit in parts of the brain¹⁰³.

DYRK1A’s kinase activity promotes α-syn pathology. Simultaneously, it contributes to disease exacerbation and progression due to increased cell death of motor and serotonergic neurons. The α-syn pathology must contribute to this accompanying neurotoxicity.

HLA-DRB1

HLA class II molecules are present on antigen presenting cells. They are responsible for T-cell activation.

VDR pathway: HLA-DRB1 has VDR-element in its promoter region.

High risk HLA-DQA1 allele is associated with pro-inflammatory profiles and reduced responsiveness to Vitamin D¹⁰⁹.

HLA-DRB1*15:01 allele transported normal and conformationally abnormal α-synuclein to the cell surface and extracellular vesicles¹²⁹. The α-syn_32-46 epitope binds to HLA-DRB1^∗15:01 allele. This interaction triggers innate and adaptive immune gene signatures in the gut¹⁰⁴.

Certain polymorphisms in HLA-DRB1 are protective against PD¹¹⁰.

The HLA-DRB1*07:01 allele was associated with anxiety¹³⁰.

The HLA molecules sensitize T-cells against α-syn and mediate an inflammatory environment necessary to mount an immune response. However, chronic inflammation in the brain is neurotoxic and may correlate with exacerbated disease symptoms.

HLA-DQA1

Higher DQA1 allele frequency was associated with PD susceptibility¹¹¹.

Meta-analysis of 27 studies reported increased immune cells in depression, including CD4+ and CD8 + T-cells¹³¹.