A feedback loop between dipeptide repeat protein, TDP-43 and Karyopherin-alpha mediates C9ORF72-related neurodegeneration

Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 that causes the most common genetic form of ALS and FTD (C9ALS/FTD). Functional studies in cell and animal models have identified pathogenic mechanisms including repeat-induced RNA toxicity and accumulation of G4C2-derived dipeptide-repeat proteins (DPRs). The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived DPR but not G4C2-RNA accumulation caused TDP-43 proteinopathy that triggered onset and progression of disease in Drosophila models of C9ALS/FTD. Timing and extent of TDP-43 dysfunction was dependent on levels and identity of DPRs produced, with poly-GR causing early and poly-GA/poly-GP causing late onset of disease. Accumulating cytosolic, but not insoluble aggregated TDP-43 caused Karyopherin-α2/4 (KPNA2/4) pathology, increased levels of DPRs and enhanced G4C2-related toxicity. Comparable KPNA4 pathology was observed in both sporadic FTD and C9ALS/FTD patient brains characterised by its nuclear depletion and cytosolic accumulation, irrespective of TDP-43 or DPR aggregates. These findings identify a vicious feedback cycle for DPR-mediated TDP-43 and subsequent KPNA pathology, which becomes self-sufficient of the initiating trigger and causes C9-related neurodegeneration.