Aggregation of the nucleic acid-binding protein TDP-43 occurs via distinct routes that are coordinated with stress granule formation
Aggregation of the nucleic acid-binding protein TDP-43 occurs via distinct routes that are coordinated with stress granule formation
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DOI：
10.1074/jbc.ra118.006351
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发表时间：
2019-03-08
影响因子：
4.8
通讯作者：
Cohen, Todd J.
中科院分区：
文献类型：
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作者：
Chen, Youjun;Cohen, Todd J.
TAR DNA结合蛋白43(TDP-43)是一种核酸结合蛋白，它的聚集代表了肌萎缩侧索硬化症(ALS)和相关蛋白病变的定义病理。最近的研究表明，细胞质应激颗粒(SGS)可能是促进TDP-43聚集的枢纽。在这里，使用细胞分级，生化分析和组织学分析，我们表明，针对细胞质的TDP-43有多种命运。虽然TDP-43亚群确实被招募到SGS中，但成熟的聚集TDP-43，与容易聚集的TDP-43变体或暴露在氧化应激下，产生不同的TDP-43包涵体，令人惊讶的是没有SGS。与此观察一致的是，我们发现ALS患者运动神经元的TDP-43病理中主要排除了SG成分。我们通过表达脆性X蛋白(FMRP)产生了从头开始的SGS，发现SGS不是直接结合TDP-43聚集体，而是可以隔离蛋白稳定因子组蛋白去乙酰基酶6(HDAC6)，从而阻碍TDP-43从细胞中清除。这些发现表明，SGS形成了不同的细胞质结构，可以间接地增强TDP-43的聚集。因此，抑制SG形成的治疗方法可能在抑制ALS患者和相关TDP-43蛋白病患者的TDP-43介导的毒性方面有效。
TAR DNA-binding protein 43 (TDP-43) is a nucleic acid-binding protein, and its aggregation represents the defining pathology in amyotrophic lateral sclerosis (ALS) and related proteinopathies. Recent studies implicate cytoplasmic stress granules (SGs) as hubs that may facilitate TDP-43 aggregation. Here, using cellular fractionation, biochemical analyses, and histological assays, we show that TDP-43 targeted to the cytoplasm has multiple fates. Whereas a TDP-43 subpopulation is indeed recruited to SGs, mature aggregated TDP-43, produced with aggregate-prone TDP-43 variants or exposure to oxidative stress, generates distinct TDP-43 inclusions that are surprisingly devoid of SGs. Consistent with this observation, we found that SG components are predominantly excluded from TDP-43 pathology in motor neurons from individuals with ALS. We generated de novo SGs by expressing the fragile X protein (FMRP) and found that rather than directly engaging TDP-43 aggregates, SGs can sequester the proteostasis factor histone deacetylase 6 (HDAC6) and thereby impede TDP-43 clearance from cells. These findings indicate that SGs form distinct cytoplasmic structures that can indirectly enhance TDP-43 aggregation. Therapeutic approaches that inhibit SG formation may therefore be effective at suppressing TDP-43-mediated toxicity in patients with ALS and related TDP-43 proteinopathies.