2. Academic Validation
  3. Maintenance of neuronal TDP-43 expression requires axonal lysosome transport

Maintenance of neuronal TDP-43 expression requires axonal lysosome transport

  • bioRxiv. 2025 Jun 30:2024.09.30.615241. doi: 10.1101/2024.09.30.615241.
Veronica H Ryan 1 2,  Sydney Lawton 1,  Joel F Reyes 1,  James Hawrot 1,  Ashley M Frankenfield 3,  Sahba Seddighi 1,  Daniel M Ramos 2,  Jacob Epstein 2,  Faraz Faghri 2 4,  Nicholas L Johnson 2 4,  Jizhong Zou 5,  Martin Kampmann 6,  John Replogle 1,  Yue A Qi 2,  Hebao Yuan 1,  Kory R Johnson 1,  Dragan Maric 1,  Ling Hao 7,  Mike A Nalls 2 4,  Michael E Ward 1
Affiliations

Affiliations

  • 1 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 2 Center for Alzheimer's and Related Dementias, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
  • 3 Department of Chemistry, George Washington University, Washington, DC, USA.
  • 4 DataTecnica, Washington, DC, USA.
  • 5 National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • 6 Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • 7 Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA.
PMID: 39803527 DOI: 10.1101/2024.09.30.615241
Abstract

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.

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