Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons

Journal article

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 lysosome location is required for proper protein turnover. As such, lysosome location and function are crucial for maintaining TDP-43 protein levels in neurons

Authors: Hasan, S; Fernandopulle, MS; Humble, SW; Frankenfield, AM; Li, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Molecular Neurodegeneration
• Volume: 18
• Issue: 1
• Pages: 87-87
• Article number: 87
• Publication date: 2023-11-16
• DOI: 10.1186/s13024-023-00673-w
• EISSN: 1750-1326
• ISSN: 1750-1326
• Language: English
• Keywords: Gene; Proteomics; Neurodegeneration; Proteostasis; Biology; Medicine; Biochemistry; Batten disease; Lysosome; Neuronal ceroid lipofuscinosis; Pathology; Enzyme; Neuroscience; Cell biology