Systematic Lipidomics Analysis Reveals Protein-Specific Lipid Signatures in C. elegans Models of Proteotoxicity-Related Neurodegeneration

Pranjal Madhav Dhat

Mentor: Dr.Priyanka Joshi, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center.

Date/Time: August 22nd, 2025 at 11:15 AM.

Abstract: Neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's disease are characterized by progressive cognitive and motor decline driven by pathological protein misfolding and aggregation. Emerging evidence suggests that dysregulation of lipid metabolism plays a critical role in disease pathogenesis, yet comprehensive lipid profiling across different proteotoxicity models remains understudied. Caenorhabditis elegans provides an ideal platform for systematic investigation of proteotoxicity-associated lipid alterations due to its short lifespan, well-characterized aging biology, genetic tractability, and optical transparency enabling real-time visualization of protein aggregates.

This study employed untargeted LC-MS-based lipidomics to systematically profile five C. elegans strains: muscle-specific models expressing human disease-associated proteins (α-synuclein, polyglutamine, and GMC), the neuronal strain CL2355, and wildtype N2 controls. We applied an integrative analytical framework combining multivariate statistical approaches with pathway mapping to identify significantly altered lipids and elucidate their functional relationships to disease mechanisms.

Our analysis revealed significant alterations in lipid signatures in the α-synuclein-expressing muscle model, demonstrating protein-specific lipid dysregulation associated with Parkinson's disease-related proteotoxicity. These findings provide novel mechanistic insights into lipid-protein interactions during α-synuclein aggregation and establish a foundation for biomarker validation and therapeutic target identification in Parkinson's disease. The demonstrated utility of C. elegans as a platform for proteotoxicity research provides a scalable framework for future investigations into lipid-mediated mechanisms underlying protein misfolding diseases.

Keywords: Protein misfolding diseases, Lipid Metabolism, Caenorhabditis elegans model, biomarkers, lipidomics