美国加州大学圣地亚哥分校Don W. Cleveland和Elizabeth Villa研究小组合作发现，分子伴侣HSP70与不结合RNA的TDP-43协调形成了核内液态凝集物。相关论文于2020年12月17日发表在《科学》杂志上。

研究人员发现RNA结合缺陷型TDP-43（由神经变性突变或RNA识别基序翻译后乙酰化造成）促使TDP-43分解成具有液体核心的核内液滴。研究人员将这些液滴命名为异构体，其外壳能发生双折射，这是液晶形成的证据。

利用数学建模，研究人员确定液态核的主要成分是HSP70伴侣蛋白，其依赖ATP活性维持了外壳和液体核的流动性。为了模拟与衰老相关蛋白酶体活性降低的情形，研究发现抑制神经元细胞中蛋白酶体的功能可以诱导TDP-43液滴的产生。当ATP含量降低时，这些结构转化为聚集体。因此，乙酰化、HSP70和蛋白酶体活性协同调节TDP-43相分离和凝胶/固相转化。

据了解，RNA结合蛋白TDP-43在与年龄有关的神经退行性疾病中形成核内或胞质聚集体。

附：英文原文

Title: HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells

Author: Haiyang Yu, Shan Lu, Kelsey Gasior, Digvijay Singh, Sonia Vazquez-Sanchez, Olga Tapia, Divek Toprani, Melinda S. Beccari, John R. Yates, Sandrine Da Cruz, Jay M. Newby, Miguel Lafarga, Amy S. Gladfelter, Elizabeth Villa, Don W. Cleveland

Issue&Volume: 2020/12/17

Abstract: The RNA-binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. Here we found that RNA-binding deficient TDP-43 (produced by neurodegeneration-causing mutations or post-translational acetylation in its RNA recognition motifs) drove TDP-43 de-mixing into intranuclear liquid spherical shells with liquid cores. We named these droplets anisosomes, whose shells exhibited birefringence, evidence of liquid crystal formation. Guided by mathematical modeling, we identified the major components of the liquid core to be HSP70 family chaperones, whose ATP-dependent activity maintained the liquidity of shells and cores. In vivo proteasome inhibition within neurons, to mimic aging-related reduction of proteasome activity, induced TDP-43-containing spherical shells. These structures converted into aggregates when ATP levels were reduced. Thus, acetylation, HSP70, and proteasome activities regulate TDP-43 phase separation and conversion into a gel/solid phase.

DOI: 10.1126/science.abb4309

Source: https://science.sciencemag.org/content/early/2020/12/16/science.abb4309