Fig. 8: α-syn as a convergent point between depression and Parkinson’s Disease.

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.