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
  • 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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