DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation.
DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation.
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DOI：
10.3390/ijms22083985
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发表时间：
2021-04-13
影响因子：
5.6
通讯作者：
Tsuboi Y
中科院分区：
文献类型：
--
作者：
Deshimaru M;Kinoshita-Kawada M;Kubota K;Watanabe T;Tanaka Y;Hirano S;Ishidate F;Hiramoto M;Ishikawa M;Uehara Y;Okano H;Hirose S;Fujioka S;Iwasaki K;Yuasa-Kawada J;Mishima T;Tsuboi Y
包括肌萎缩侧索硬化症在内的多种神经退行性疾病的常见病理特征是核 RNA 结合蛋白 TDP-43 的细胞质错误定位和聚集。 Perry 病表现为遗传性非典型帕金森病，是一种 TDP-43 蛋白病。致病基因 DCTN1 编码 dynactin 复合物的最大亚基。动力蛋白与基于微管的运动细胞质动力蛋白结合，是动力蛋白介导的长距离逆行运输所必需的。与 Perry 疾病相关的错义突变（例如 p.G71A）位于 CAP-Gly 结构域内，并损害 DCTN1 的微管结合能力。然而，此类 DCTN1 突变导致 TDP-43 蛋白病的分子机制仍不清楚。我们发现 DCTN1 与 TDP-43 结合。使用一组截短突变体进行的生化分析表明，DCTN1 CAP-Gly-碱性超结构域、dynactin 结构域和 C 端区域与 TDP-43 相互作用，优先通过其 C 端区域。值得注意的是，p.G71A 突变影响了 DCTN1 的 TDP-43 相互作用能力。 DCTN1G71A、动力蛋白结构域片段或 C 末端片段（而非 CAP-Gly 碱性片段）的过表达诱导 TDP-43 的细胞质错误定位和聚集，表明 DCTN1 的 TDP-43 相互作用结构域之间存在功能模块化。因此，我们确定 DCTN1 是 TDP-43 细胞质-核运输中的新参与者，并表明 DCTN1-TDP-43 相互作用的失调会触发 TDP-43 的错误定位和聚集，从而为 Perry 病和其他 TDP-43 蛋白病的病理机制提供见解。
A common pathological hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis, is cytoplasmic mislocalization and aggregation of nuclear RNA-binding protein TDP-43. Perry disease, which displays inherited atypical parkinsonism, is a type of TDP-43 proteinopathy. The causative gene DCTN1 encodes the largest subunit of the dynactin complex. Dynactin associates with the microtubule-based motor cytoplasmic dynein and is required for dynein-mediated long-distance retrograde transport. Perry disease-linked missense mutations (e.g., p.G71A) reside within the CAP-Gly domain and impair the microtubule-binding abilities of DCTN1. However, molecular mechanisms by which such DCTN1 mutations cause TDP-43 proteinopathy remain unclear. We found that DCTN1 bound to TDP-43. Biochemical analysis using a panel of truncated mutants revealed that the DCTN1 CAP-Gly-basic supradomain, dynactin domain, and C-terminal region interacted with TDP-43, preferentially through its C-terminal region. Remarkably, the p.G71A mutation affected the TDP-43-interacting ability of DCTN1. Overexpression of DCTN1G71A, the dynactin-domain fragment, or C-terminal fragment, but not the CAP-Gly-basic fragment, induced cytoplasmic mislocalization and aggregation of TDP-43, suggesting functional modularity among TDP-43-interacting domains of DCTN1. We thus identified DCTN1 as a new player in TDP-43 cytoplasmic-nuclear transport, and showed that dysregulation of DCTN1-TDP-43 interactions triggers mislocalization and aggregation of TDP-43, thus providing insights into the pathological mechanisms of Perry disease and other TDP-43 proteinopathies.
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影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
通讯作者：
Rossoll W
影响因子：
30.8
作者：
Farrer MJ;Hulihan MM;Kachergus JM;Dächsel JC;Stoessl AJ;Grantier LL;Calne S;Calne DB;Lechevalier B;Chapon F;Tsuboi Y;Yamada T;Gutmann L;Elibol B;Bhatia KP;Wider C;Vilariño-Güell C;Ross OA;Brown LA;Castanedes-Casey M;Dickson DW;Wszolek ZK
通讯作者：
Wszolek ZK
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.
影响因子：
16.2
作者：
Alami NH;Smith RB;Carrasco MA;Williams LA;Winborn CS;Han SSW;Kiskinis E;Winborn B;Freibaum BD;Kanagaraj A;Clare AJ;Badders NM;Bilican B;Chaum E;Chandran S;Shaw CE;Eggan KC;Maniatis T;Taylor JP
通讯作者：
Taylor JP
影响因子：
21.3
作者：
Giannakakou, P;Sackett, DL;Fojo, T
通讯作者：
Fojo, T