Isoform-Specific Pathways in neurodegeneration: convergence on impaired autophagosome-lysosome fusion

Professor Justin O’Sullivan from the Liggins Institute at the University of Auckland in New Zealand will visit our Center for Eukaryotic Gene Regulation next Wed morning and present a 45 min seminar (35 min talk, 10 min Q&A).

Parkinson's disease (PD) pathogenesis involves complex interactions between genetic factors. We employed two-sample Mendelian randomization (MR) integrating tissue-specific gene regulatory networks to identify causal genes and regulatory elements modulating PD risk. Two-sample MR analysis identified 79 putative causal genes for PD. A subset of the 79 causal genes were enriched within chr17q21.31 and chr16p11.2 cytobands that have been previously linked to neurodevelopmental disorders. Functional enrichment analysis of the 79 genes revealed autophagosome-lysosome fusion as a key process. Ten genes (ELOVL7, HSD3B7, PLEKHM1, PRSS53, SNCA, STX1B, STX4, ZSWIM7, LINC02210, and RP11-1072A3.3) showed causal associations with tissue-specific expression patterns driving risk or protection for PD. Further investigation into their tissue-specific isoform expression profile revealed isoform-specific contributions to disease risk (or protection). Notably, our in-depth analysis of causal gene expression profiles highlights isoform-specific contributions converging on the autophagosome-lysosome fusion pathway—a critical process that bridges neurobiology with metabolic and gastrointestinal health. These findings refine our understanding of inherited susceptibility to neurodegeneration and illuminate potential mechanisms through which environmental factors might influence disease trajectories. We contend that this innovative approach offers valuable insights for scientists and clinicians, fostering new avenues for translational research and therapeutic intervention.