Fig. 3: α-syn at the nexus of PD and depression pathology.
From: α-synuclein in Parkinson’s disease: a central point of convergence with depression
(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.
