HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS.
HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS.
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DOI：
10.3389/fcell.2021.809942
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhang YJ
中科院分区：
文献类型：
--
作者：
Del Rosso G;Carlomagno Y;Todd TW;Jones CY;Prudencio M;Daughrity LM;Yue M;Jansen-West K;Tong J;Shao W;Wu Y;Castanedes-Casey M;Tabassian L;Oskarsson B;Ling K;Rigo F;Dickson DW;Yao TP;Petrucelli L;Cook CN;Zhang YJ
9号染色体开放阅读框72（C9 orf 72）中重复扩增的异常翻译是额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）的最常见原因，其导致毒性二肽重复（DPR）蛋白在中枢神经系统中积累。HDAC 6特异性地与聚（GA）相互作用，并与患者组织和该疾病的小鼠模型（c9 FTD/ALS）中的包涵体共定位。HDAC 6的过表达增加了培养细胞中的poly（GA）水平，这与HDAC 6脱乙酰酶活性无关，表明HDAC 6可以通过依赖于它们的物理相互作用的机制来调节poly（GA）病理学。此外，通过立体定位注射反义寡核苷酸降低HDAC 6表达显著减少了c9 FTD/ALS小鼠中聚（GA）包涵体的数量。这些结果表明，降低HDAC 6水平的药物在c9 FTD/ALS中可能具有治疗价值。
The aberrant translation of a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), results in the accumulation of toxic dipeptide repeat (DPR) proteins in the central nervous system We have found that, among the sense DPR proteins, HDAC6 specifically interacts with the poly (GA) and co-localizes with inclusions in both patient tissue and a mouse model of this disease (c9FTD/ALS). Overexpression of HDAC6 increased poly (GA) levels in cultured cells independently of HDAC6 deacetylase activity, suggesting that HDAC6 can modulate poly (GA) pathology through a mechanism that depends upon their physical interaction. Moreover, decreasing HDAC6 expression by stereotaxic injection of antisense oligonucleotides significantly reduced the number of poly (GA) inclusions in c9FTD/ALS mice. These findings suggest that pharmacologically reducing HDAC6 levels could be of therapeutic value in c9FTD/ALS.
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影响因子：
12.7
作者：
Janocko NJ;Brodersen KA;Soto-Ortolaza AI;Ross OA;Liesinger AM;Duara R;Graff-Radford NR;Dickson DW;Murray ME
通讯作者：
Murray ME
影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
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：
15.1
作者：
Ohki Y;Wenninger-Weinzierl A;Hruscha A;Asakawa K;Kawakami K;Haass C;Edbauer D;Schmid B
通讯作者：
Schmid B
影响因子：
17.1
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
通讯作者：
Petrucelli L