| Autor: |
Cook, Casey N., Wu, Yanwei, Odeh, Hana M., Gendron, Tania F., Jansen-West, Karen, del Rosso, Giulia, Yue, Mei, Jiang, Peizhou, Gomes, Edward, Tong, Jimei, Daughrity, Lillian M., Avendano, Nicole M., Castanedes-Casey, Monica, Shao, Wei, Oskarsson, Björn, Tomassy, Giulio S., McCampbell, Alexander, Rigo, Frank, Dickson, Dennis W., Shorter, James |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 9/2/2020, Vol. 12 Issue 559, p1-11, 11p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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