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Maintenance of neuronal TDP-43 expression requires axonal lysosome transport

GSE299976 Homo sapiens Expression profiling by high throughput sequencing 7 samples Submitted 2025/07/01 Platform GPL34284
Summary
TDP-43 mislocalization and pathology occurs across a range of neurodegenerative diseases, but the pathways that modulate TDP-43 in neurons are not well understood. We generated a Halo-TDP-43 knock-in iPSC line and performed a genome-wide CRISPR interference FACS-based screen to identify modifiers of TDP-43 levels in neurons. A meta-analysis of our screen and publicly available screens identified both specific hits and pathways present across multiple screens, the latter likely responsible for generic protein level maintenance. We identified BORC, a complex required for anterograde lysosome transport, as a specific modifier of TDP-43 protein, but not mRNA, levels in neurons. BORC loss led to longer half-life of TDP-43 and other proteins, suggesting lysosome location is required for proper protein turnover. As such, lysosome location and function are crucial for maintaining TDP-43 protein levels in neurons.
Published in
Maintenance of neuronal TDP-43 expression requires axonal lysosome transport
Ryan VH, Lawton S, Reyes JF et al. · eLife 2025 · PMID 40970386 · doi:10.7554/eLife.104057
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Also filed as BioProject PRJNA1277782 and SRA study SRP592578. Searching any of these in the dataset finder brings you back here.

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