PT  - JOURNAL ARTICLE
AU  - Cook, Casey N.
AU  - Wu, Yanwei
AU  - Odeh, Hana M.
AU  - Gendron, Tania F.
AU  - Jansen-West, Karen
AU  - del Rosso, Giulia
AU  - Yue, Mei
AU  - Jiang, Peizhou
AU  - Gomes, Edward
AU  - Tong, Jimei
AU  - Daughrity, Lillian M.
AU  - Avendano, Nicole M.
AU  - Castanedes-Casey, Monica
AU  - Shao, Wei
AU  - Oskarsson, Björn
AU  - Tomassy, Giulio S.
AU  - McCampbell, Alexander
AU  - Rigo, Frank
AU  - Dickson, Dennis W.
AU  - Shorter, James
AU  - Zhang, Yong-Jie
AU  - Petrucelli, Leonard
TI  - <em>C9orf72</em> poly(GR) aggregation induces TDP-43 proteinopathy
AID  - 10.1126/scitranslmed.abb3774
DP  - 2020 Sep 02
TA  - Science Translational Medicine
PG  - eabb3774
VI  - 12
IP  - 559
4099  - http://stm.sciencemag.org/content/12/559/eabb3774.short
4100  - http://stm.sciencemag.org/content/12/559/eabb3774.full
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.