TDP-43 Is Intrinsically Aggregation-prone, and Amyotrophic Lateral Sclerosis-linked Mutations Accelerate Aggregation and Increase Toxicity
TDP-43 Is Intrinsically Aggregation-prone, and Amyotrophic Lateral Sclerosis-linked Mutations Accelerate Aggregation and Increase Toxicity
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DOI：
10.1074/jbc.m109.010264
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发表时间：
2009-07-24
影响因子：
4.8
通讯作者：
Gitler, Aaron D.
中科院分区：
文献类型：
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作者：
Johnson, Brian S.;Snead, David;Gitler, Aaron D.
含有TDP-43及其C-末端片段的非淀粉样蛋白、泛素化细胞质内含物是肌萎缩侧索硬化症（ALS）（一种致命的运动神经元疾病）和具有泛素阳性内含物的额颞叶变性（FTLD-U）的病理标志。重要的是，TDP-43突变与散发性和非SOD 1家族性ALS有关。然而，TDP-43不是疾病相关包涵体中唯一的蛋白质，TDP-43是否错误折叠或仅仅被其他聚集组分隔离尚不清楚。在这里，我们报告说，在没有其他成分，TDP-43自发形成聚集体轴承显着的超微结构相似性TDP-43存款在ALS FTLD-U患者的变性神经元。TDP-43的C-末端结构域对于自发聚集至关重要。该结构域中的几个ALS相关TDP-43突变（Q331 K、M337 V、Q343 R、N345 K、R361 S和N390 D）增加了TDP-43聚集体的数量并促进了体内毒性。重要的是，在体内促进毒性的突变在体外加速纯TDP-43的聚集。因此，TDP-43本质上是易于聚集的，并且其毒性错误折叠轨迹的倾向通过特定的ALS连锁突变而加剧。
Non-amyloid, ubiquitinated cytoplasmic inclusions containing TDP-43 and its C-terminal fragments are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Importantly, TDP-43 mutations are linked to sporadic and non-SOD1 familial ALS. However, TDP-43 is not the only protein in disease-associated inclusions, and whether TDP-43 misfolds or is merely sequestered by other aggregated components is unclear. Here, we report that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP-43 deposits in degenerating neurons of ALS FTLD-U patients. The C-terminal domain of TDP-43 is critical for spontaneous aggregation. Several ALS-linked TDP-43 mutations within this domain (Q331K, M337V, Q343R, N345K, R361S, and N390D) increase the number of TDP-43 aggregates and promote toxicity in vivo. Importantly, mutations that promote toxicity in vivo accelerate aggregation of pure TDP-43 in vitro. Thus, TDP-43 is intrinsically aggregation-prone, and its propensity for toxic misfolding trajectories is accentuated by specific ALS-linked mutations.