biostudies-literatureRyan VHNational Institute of Neurological Disorders and StrokeNIA NIH HHSNINDS NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHSNational Institute on AgingRP104057https://www.ebi.ac.uk/biostudies/studies/S-EPMC12448747biostudies-literatureUnknown14TDP-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 human induced pluripotent stem cell (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 lysoeLifeMaintenance of neuronal TDP-43 expression requires axonal lysosome transport.PMC12448747Fi2GM142475R01NS121608R01 NS121608Intramural Research ProgramMaric DZou JJohnson KWard MEHao LRamos DMYuan HJohnson NLKampmann MQi YAReplogle JLawton SFrankenfield AMSeddighi SFaghri FRyan VHReyes JFEpstein JNalls MAHawrot JfalseMaintenance of neuronal TDP-43 expression requires axonal lysosome transport.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 human induced pluripotent stem cell (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 lyso2025-01-01T00:00:00Z2025 Sep2026-06-03T14:39:25.737Z2026-05-29T03:05:33.921ZS-EPMC124487474097038610.7554/eLife.104057