Intihar Taylor A, Martinez Elisa A, Gomez-Pastor Rocio
Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States.
Department of Biochemistry and Molecular Biology, Dickinson College, Carlisle, PA, United States.
Front Cell Neurosci. 2019 Mar 19;13:103. doi: 10.3389/fncel.2019.00103. eCollection 2019.
Huntington's disease (HD) is a neurodegenerative disease caused by an expanded CAG repeat in the huntingtin () gene, causing the protein to misfold and aggregate. HD progression is characterized by motor impairment and cognitive decline associated with the preferential loss of striatal medium spiny neurons (MSNs). The mechanisms that determine increased susceptibility of MSNs to mutant HTT (mHTT) are not fully understood, although there is abundant evidence demonstrating the importance of mHTT mediated mitochondrial dysfunction in MSNs death. Two main transcription factors, p53 and peroxisome proliferator co-activator PGC-1α, have been widely studied in HD for their roles in regulating mitochondrial function and apoptosis. The action of these two proteins seems to be interconnected. However, it is still open to discussion whether p53 and PGC-1α dependent responses directly influence each other or if they are connected a third mechanism. Recently, the stress responsive transcription factor HSF1, known for its role in protein homeostasis, has been implicated in mitochondrial function and in the regulation of PGC-1α and p53 levels in different contexts. Based on previous reports and our own research, we discuss in this review the potential role of HSF1 in mediating mitochondrial dysfunction in HD and propose a unifying mechanism that integrates the responses mediated by p53 and PGC-1α in HD HSF1.
亨廷顿舞蹈症（HD）是一种神经退行性疾病，由亨廷顿蛋白（HTT）基因中CAG重复序列扩增所致，会导致该蛋白错误折叠并聚集。HD的病程特点是运动障碍和认知衰退，这与纹状体中型多棘神经元（MSNs）的选择性丧失有关。尽管有大量证据表明突变型HTT（mHTT）介导的线粒体功能障碍在MSNs死亡中起重要作用，但决定MSNs对mHTT易感性增加的机制尚未完全明确。两种主要的转录因子，即p53和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α），因其在调节线粒体功能和细胞凋亡中的作用，在HD研究中受到广泛关注。这两种蛋白的作用似乎相互关联。然而，p53和PGC-1α依赖的反应是直接相互影响，还是通过第三种机制联系起来，仍有待探讨。最近，以其在蛋白质稳态中的作用而闻名的应激反应转录因子HSF1，在不同情况下与线粒体功能以及PGC-1α和p53水平的调节有关。基于先前的报道和我们自己的研究，我们在本综述中讨论了HSF1在介导HD线粒体功能障碍中的潜在作用，并提出了一种统一机制，该机制整合了HD中由p53和PGC-1α介导的反应以及HSF1。
