RT Journal Article SR Electronic T1 C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy JF Science Translational Medicine FD American Association for the Advancement of Science SP eabb3774 DO 10.1126/scitranslmed.abb3774 VO 12 IS 559 A1 Cook, Casey N. A1 Wu, Yanwei A1 Odeh, Hana M. A1 Gendron, Tania F. A1 Jansen-West, Karen A1 del Rosso, Giulia A1 Yue, Mei A1 Jiang, Peizhou A1 Gomes, Edward A1 Tong, Jimei A1 Daughrity, Lillian M. A1 Avendano, Nicole M. A1 Castanedes-Casey, Monica A1 Shao, Wei A1 Oskarsson, Björn A1 Tomassy, Giulio S. A1 McCampbell, Alexander A1 Rigo, Frank A1 Dickson, Dennis W. A1 Shorter, James A1 Zhang, Yong-Jie A1 Petrucelli, Leonard YR 2020 UL http://stm.sciencemag.org/content/12/559/eabb3774.abstract AB 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.