Label-Free Proteomics of α-Synuclein-Expressing Caenorhabditis elegans Model Uncovers Conserved Pathophysiological Pathways in Parkinson's Disease

Parkinsons disease (PD) is the second most prevalent neurodegenerative disease in the elderly population, characterized by a wide variety of motor and non-motor symptoms. Its complex biochemical and molecular mechanisms make it challenging to study PD directly in patients or to replicate it in vitro, underscoring the need for careful model characterization to advance translational research. The free-living nematode Caenorhabditis elegans has been widely used in neuroscience studies. Technological advancements enabled the development of transgenic strains that mimic aspects of neurodegenerative diseases, such as the OW13 strain [grk-1(ok1239) X; pkIs2386 IV (unc-54p::alpha-synuclein::YFP + unc-119(+))], which expresses human -synuclein in body wall muscle cells in a sensitized G-protein coupled receptor kinase-deficient background. This study conducted an exploratory proteomic analysis of the OW13 strain. A cross-species comparative analysis using post-mortem substantia nigra proteomics from PD individuals identified a convergent signature of 76 conserved C. elegans proteins, corresponding to 70 human orthologs, derived from the 373 DAPs. Among these conserved candidates, 68 proteins were upregulated, and 8 were downregulated. Functional enrichment linked these DAPs to the tricarboxylic acid cycle, mitochondrial function, and protein quality control, suggesting that -synuclein aggregation triggers a broad proteostatic and bioenergetic remodeling resembling PD pathophysiology. This first proteomic and cross-species characterization of the OW13 strain strongly supports C. elegans as a robust PD model.