C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy

See allHide authors and affiliations

Science Translational Medicine  02 Sep 2020:
Vol. 12, Issue 559, eabb3774
DOI: 10.1126/scitranslmed.abb3774

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Unraveling protein clumping

Repeat expansion in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders with common features. A proportion of patients with ALS/FTD present cytoplasmic TDP-43 aggregates in the brain. The mechanisms mediating the formation of TDP-43 aggregates are unclear. Now, Cook et al. show that a poly glycine-arginine protein [poly(GR)] produced by the repeat expansion enhanced the formation of TDP-43 aggregates in vitro and in vivo in mice by altering nucleocytoplasmic transport. Targeting the repeat expansion with a specific antisense oligonucleotide reduced the formation of TDP-43 aggregates. The results shine the light on the mechanisms mediating the formation of toxic aggregates in neurodegenerative diseases.


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.

View Full Text

Stay Connected to Science Translational Medicine