Biology and Pathobiology of TDP-43 and Emergent Therapeutic Strategies.
Biology and Pathobiology of TDP-43 and Emergent Therapeutic Strategies.
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DOI：
10.1101/cshperspect.a024554
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发表时间：
2017-09-01
影响因子：
5.4
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
Guo L;Shorter J
胞浆TDP-43的错误定位和聚集是肌萎缩侧索硬化和额颞叶变性的病理标志。TDP-43是一种RNA结合蛋白（RBP），具有促进TDP-43错误折叠的朊病毒样结构域（PrLD）。PrLD具有与各种酵母蛋白（包括Sup 35）的典型朊病毒结构域的组成相似性。引人注目的是，致病的TDP-43突变几乎完全存在于PrLD中，并且可以增强TDP-43的错误折叠和毒性。另外约70种人类RBP携带PrLD，包括FUS，TAF 15，EWSR 1，hnRNPA 1和hnRNPA 2，它们已在神经退行性疾病的病因学中浮出水面。重要的是，PrLD使RBP功能和介导的相变，分区功能的核糖核蛋白区室。然而，这种PrLD活性使RBP倾向于填充可能传播疾病的有害寡聚体或自模板原纤维，并且与疾病相关的PrLD突变可能加剧这种风险。已经出现了几种对抗TDP-43蛋白质病的策略，包括基于Hsp 104的工程增强的蛋白质解聚剂。
Cytoplasmic TDP-43 mislocalization and aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is an RNA-binding protein (RBP) with a prion-like domain (PrLD) that promotes TDP-43 misfolding. PrLDs possess compositional similarity to canonical prion domains of various yeast proteins, including Sup35. Strikingly, disease-causing TDP-43 mutations reside almost exclusively in the PrLD and can enhance TDP-43 misfolding and toxicity. Another ~70 human RBPs harbor PrLDs, including FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, which have surfaced in the etiology of neurodegenerative diseases. Importantly, PrLDs enable RBP function and mediate phase transitions that partition functional ribonucleoprotein compartments. This PrLD activity, however, renders RBPs prone to populating deleterious oligomers or self-templating fibrils that might spread disease, and disease-linked PrLD mutations can exacerbate this risk. Several strategies have emerged to counter TDP-43 proteinopathies, including engineering enhanced protein disaggregases based on Hsp104.
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影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
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Finkbeiner, Steven
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作者：
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通讯作者：
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3.5
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作者：
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通讯作者：
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DOI：
10.1073/pnas.1121005109
发表时间：
2012-06-12
影响因子：
11.1
作者：
Bulawa, Christine E.;Connelly, Stephen;Labaudiniere, Richard
通讯作者：
Labaudiniere, Richard