A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration

Daniel A. Solomon, Alan Stepto, Wing Hei Au, Yoshitsugu Adachi, Danielle C. Diaper, Rachel Hall, Anjeet Rekhi, Adel Boudi, Paraskevi Tziortzouda, Youn Bok Lee, Bradley Smith, Jessika C. Bridi, Greta Spinelli, Jonah Dearlove, Dickon M. Humphrey, Jean Marc Gallo, Claire Troakes, Manolis Fanto, Matthias Soller, Boris RogeljRichard B. Parsons, Christopher E. Shaw, T. Hortobágyi, Frank Hirth

Research output: Contribution to journalArticle

11 Citations (Scopus)


Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9orf72 that causes the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia (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. The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived dipeptide-repeat protein 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 dipeptide-repeat proteins 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 dipeptide-repeat proteins and enhanced G4C2-related toxicity. Comparable KPNA4 pathology was observed in both sporadic frontotemporal dementia and C9ALS/FTD patient brains characterized by its nuclear depletion and cytosolic accumulation, irrespective of TDP-43 or dipeptide-repeat protein aggregates. These findings identify a vicious feedback cycle for dipeptide-repeat protein-mediated TDP-43 and subsequent KPNA pathology, which becomes self-sufficient of the initiating trigger and causes C9-related neurodegeneration.

Original languageEnglish
Pages (from-to)2908-2924
Number of pages17
Issue number10
Publication statusPublished - Oct 1 2018



  • amyotrophic lateral sclerosis
  • C9ORF72
  • frontotemporal dementia
  • karyopherin
  • TDP-43

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Solomon, D. A., Stepto, A., Au, W. H., Adachi, Y., Diaper, D. C., Hall, R., Rekhi, A., Boudi, A., Tziortzouda, P., Lee, Y. B., Smith, B., Bridi, J. C., Spinelli, G., Dearlove, J., Humphrey, D. M., Gallo, J. M., Troakes, C., Fanto, M., Soller, M., ... Hirth, F. (2018). A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration. Brain, 141(10), 2908-2924. https://doi.org/10.1093/brain/awy241