C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy.
C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy.
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DOI：
10.1126/scitranslmed.abb3774
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发表时间：
2020-09-02
影响因子：
17.1
通讯作者：
Petrucelli L
中科院分区：
文献类型：
--
作者：
Cook CN;Wu Y;Odeh HM;Gendron TF;Jansen-West K;Del Rosso G;Yue M;Jiang P;Gomes E;Tong J;Daughrity LM;Avendano NM;Castanedes-Casey M;Shao W;Oskarsson B;Tomassy GS;McCampbell A;Rigo F;Dickson DW;Shorter J;Zhang YJ;Petrucelli L
TAR dna结合蛋白43 （TDP-43）内含物是额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）的病理标志，包括由C9orf72基因G4C2重复扩增（c9FTD/ALS）引起的病例。为了深入了解C9orf72突变与TDP-43病理之间的联系，我们证明了从扩展的G4C2重复序列翻译的甘氨酸-精氨酸重复序列蛋白[poly(GR)]足以促进内源性TDP-43的聚集。特别是，毒性多聚（GR）蛋白以不依赖rna的方式介导全长TDP-43的隔离，诱导胞质TDP-43包涵体的形成。此外，在GFP-(GR)200小鼠中，poly（GR）引起核胞质转运因子和核孔复合物蛋白的错定位。这些错误定位事件导致内源性TDP-43在细胞质中异常积累，并与poly（GR）共聚集。最后，我们证明了用靶向重复的反义寡核苷酸治疗G4C2重复表达小鼠可降低poly（GR）负荷，这伴随着TDP-43病理和神经变性的减少，包括血浆神经丝光（NFL）浓度的降低。这些结果有助于阐明poly（GR）驱动TDP-43蛋白病变的机制，证实g4c2靶向治疗可减少体内TDP-43病理，并证明血浆NFL的改变为疾病改善治疗的治疗效果提供了见解。
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.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
4.8
作者：
Johnson, Brian S.;Snead, David;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.
影响因子：
12.7
作者：
Mackenzie, Ian R.;Arzberger, Thomas;Neumann, Manuela
通讯作者：
Neumann, Manuela
影响因子：
15.1
作者：
Chew, Jeannie;Cook, Casey;Petrucelli, Leonard
通讯作者：
Petrucelli, Leonard
DOI：
10.1126/science.aaa9344
发表时间：
2015-06-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chew J;Gendron TF;Prudencio M;Sasaguri H;Zhang YJ;Castanedes-Casey M;Lee CW;Jansen-West K;Kurti A;Murray ME;Bieniek KF;Bauer PO;Whitelaw EC;Rousseau L;Stankowski JN;Stetler C;Daughrity LM;Perkerson EA;Desaro P;Johnston A;Overstreet K;Edbauer D;Rademakers R;Boylan KB;Dickson DW;Fryer JD;Petrucelli L
通讯作者：
Petrucelli L