Neurodegenerative Disease Proteinopathies Are Connected to Distinct Histone Post-translational Modification Landscapes.
Neurodegenerative Disease Proteinopathies Are Connected to Distinct Histone Post-translational Modification Landscapes.
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DOI：
10.1021/acschemneuro.7b00297
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发表时间：
2018-04-18
影响因子：
5
通讯作者：
Torrente MP
中科院分区：
文献类型：
--
作者：
Chen K;Bennett SA;Rana N;Yousuf H;Said M;Taaseen S;Mendo N;Meltser SM;Torrente MP
肌萎缩侧索硬化症（ALS）和帕金森病（PD）是涉及神经元进行性变性的破坏性神经退行性疾病。诊断患有这些疾病的患者无法治愈。ALS和PD的一个显著特征是蛋白质内含物在退化神经元的细胞质中的积累;然而，构成这些内含物的特定蛋白质不同：RNA结合蛋白TDP-43和FUS在ALS中最显著，而α-突触核蛋白在PD中聚集成路易体。在这两种疾病中，遗传原因无法解释大部分病例的发生，因此，两者都被认为是散发性的。尽管越来越多的证据表明表观遗传学在ALS和PD的发生和发展中可能发挥作用，但这些疾病的表观遗传机制仍然大多未被探索。在这里，我们全面描绘组蛋白翻译后修饰（PTM）的ALS和PD酵母蛋白病模型的配置文件。值得注意的是，我们发现每个组蛋白修饰概况的不同变化。我们检测到的背景下FUS聚集最显着的变化：几个组蛋白标记的变化支持基因转录的全球减少。我们还检测到过度表达TDP-43或α-突触核蛋白的细胞中组蛋白修饰的更适度的变化。我们的研究结果强调了在神经退行性变的研究中纳入表观遗传机制的巨大需求。我们希望我们的工作将为发现更有效的治疗方法铺平道路，以治疗ALS，PD和其他神经退行性疾病患者。
Amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) are devastating neurodegenerative diseases involving the progressive degeneration of neurons. No cure is available for patients diagnosed with these diseases. A prominent feature of both ALS and PD is the accumulation of protein inclusions in the cytoplasm of degenerating neurons; however, the particular proteins constituting these inclusions vary: the RNA-binding proteins TDP-43 and FUS are most notable in ALS, while α-synuclein aggregates into Lewy bodies in PD. In both diseases, genetic causes fail to explain the occurrence of a large proportion of cases, and thus, both are considered mostly sporadic. Despite mounting evidence for a possible role of epigenetics in the occurrence and progression of ALS and PD, epigenetic mechanisms in the context of these diseases remain mostly unexplored. Here we comprehensively delineate histone post-translational modification (PTM) profiles in ALS and PD yeast proteinopathy models. Remarkably, we find distinct changes in histone modification profiles for each. We detect the most striking changes in the context of FUS aggregation: changes in several histone marks support a global decrease in gene transcription. We also detect more modest changes in histone modifications in cells overexpressing TDP-43 or α-synuclein. Our results highlight a great need for the inclusion of epigenetic mechanisms in the study of neurodegeneration. We hope our work will pave the way for the discovery of more effective therapies to treat patients suffering from ALS, PD, and other neurodegenerative diseases.
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