C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy

Casey N. Cook, Yanwei Wu, Hana M. Odeh, Tania F. Gendron, Karen Jansen-West, Giulia del Rosso, Mei Yue, Peizhou Jiang, Edward Gomes, Jimei Tong, Lillian M. Daughrity, Nicole M. Avendano, Monica Castanedes-Casey, Wei Shao, Björn Oskarsson, Giulio S. Tomassy, Alexander McCampbell, Frank Rigo, Dennis W. Dickson, James ShorterYong Jie Zhang, Leonard Petrucelli

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by G4C2 repeat expansions in the C9orf72 gene (c9FTD/ALS). Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G4C2 repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation. Moreover, in GFP-(GR)200 mice, poly(GR) caused the mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins. These mislocalization events resulted in the aberrant accumulation of endogenous TDP-43 in the cytoplasm where it co-aggregated with poly(GR). Last, we demonstrated that treating G4C2 repeat–expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration. These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that G4C2-targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.

Original languageEnglish (US)
Article number, eabb3774
JournalScience translational medicine
Issue number559
StatePublished - 2020

ASJC Scopus subject areas

  • General Medicine


Dive into the research topics of 'C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy'. Together they form a unique fingerprint.

Cite this