PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein phosphatase S (PTPσ) as a strong modifier of poly-GR-mediated toxicity. We showed that reducing PTPσ promotes the survival of both poly-GR- and poly-PR-expressing neurons by elevating phosphatidylinositol 3-phosphate (PI3P), accompanied by restored early endosomes and lysosomes. Remarkably, PTPσ knockdown or inhibition substantially rescues the PI3P-endolysosomal defects and improves the survival of C9ORF72-ALS/FTD patient-derived neurons. Furthermore, the PTPσ inhibitor diminishes GR toxicity and rescues pathological and behavioral phenotypes in mice. Overall, these findings emphasize the critical role of PI3P-mediated endolysosomal deficits induced by R-DPRs in disease pathogenesis and reveal the therapeutic potential of targeting PTPσ in C9ORF72-ALS/FTD.