The G4C2 repeat expansion in the first intron of the C9ORF72 gene (C9) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The dipeptide repeat (DPR) proteins translated from the repeat sequence initiate a cascade of cellular dysfunctions, such as protein misfolding, impaired nucleocytoplasmic transport and mitochondrial dysfunction, resulting in neurodegeneration. Poly-GR is one of the DPRs highly toxic to neurons and relevant to the disease pathogenesis.
Through CRISPR interference (CRISPRi) screening in human neurons, receptor-type tyrosine-protein phosphatase S (PTPσ) was identified as a strong modifier of poly-GR mediated toxicity. Evidence supports that decreasing PTPσ levels can enhance neuron survival by elevating phosphatidylinositol 3-phosphate (PI3P) levels. This elevation mitigates endosomal and lysosomal deficits in poly-GR expressing neurons and C9-ALS/FTD patient-derived induced pluripotent stem cell-differentiated motor neurons (C9-iMNs), indicating the therapeutic potential of targeting PTPσ in C9-ALS/FTD. Additionally, the rescue effect of applying ISP, a PTPσ inhibitor, in both in vitro and in vivo models, further underscores the significance of PTPσ in regulating poly-GR mediated neurotoxicity. These exciting findings highlight the role of PI3P in the pathogenesis of C9-ALS/FTD, offering a new direction for the therapy development of the disease.