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

Parkinson's disease (PD) is the second most common neurodegenerative disorder in older adults, presenting with both motor and non-motor symptoms. Directly studying PD in patients or replicating it in a lab setting is difficult due to its intricate biochemical and molecular processes. This highlights the importance of accurate model characterization for advancing translational research.

The Caenorhabditis elegans nematode has been extensively utilized in neuroscience research. Innovations have led to the creation of transgenic strains that replicate certain aspects of neurodegenerative diseases, such as the OW13 strain. This strain expresses human alpha-synuclein in its body wall muscle cells, specifically in a sensitized G-protein coupled receptor kinase-deficient background.

This study performed an initial proteomic examination of the OW13 strain. By comparing cross-species proteomics using post-mortem substantia nigra samples from PD patients, researchers identified a shared signature of 76 consistent C. elegans proteins, corresponding to 70 human orthologs, out of 373 DAPs. Among these shared candidates, 68 proteins were upregulated, while 8 were downregulated.

Functional enrichment associated these DAPs with the tricarboxylic acid cycle, mitochondrial function, and protein quality control, indicating that alpha-synuclein aggregation initiates a widespread proteostatic and bioenergetic remodeling process akin to PD pathophysiology. This initial proteomic and cross-species analysis of the OW13 strain strongly validates C. elegans as a reliable model for studying PD.