Piper Desiree A, Sastre Danuta, Schüle Birgitt
Parkinson's Institute and Clinical Center, Sunnyvale, CA, United States.
Front Neurosci. 2018 Apr 9;12:199. doi: 10.3389/fnins.2018.00199. eCollection 2018.
Alpha-synuclein () plays a central role in the pathogenesis of Parkinson's disease (PD) and related Lewy body disorders such as Parkinson's disease dementia, Lewy body dementia, and multiple system atrophy. Since its discovery as a disease-causing gene in 1997, alpha-synuclein has been a central point of scientific interest both at the protein and gene level. Mutations, including copy number variants, missense mutations, short structural variants, and single nucleotide polymorphisms, can be causative for PD and affect conformational changes of the protein, can contribute to changes in expression of alpha-synuclein and its isoforms, and can influence regulation of temporal as well as spatial levels of alpha-synuclein in different tissues and cell types. A lot of progress has been made to understand both the physiological transcriptional and epigenetic regulation of the alpha-synuclein gene and whether changes in transcriptional regulation could lead to disease and neurodegeneration in PD and related alpha-synucleinopathies. Although the histopathological changes in these neurodegenerative disorders are similar, the temporal and spatial presentation and progression distinguishes them which could be in part due to changes or disruption of transcriptional regulation of alpha-synuclein. In this review, we describe different genetic alterations that contribute to PD and neurodegenerative conditions and review aspects of transcriptional regulation of the alpha-synuclein gene in the context of the development of PD. New technologies, advanced gene engineering and stem cell modeling, are on the horizon to shed further light on a better understanding of gene regulatory processes and exploit them for therapeutic developments.
α-突触核蛋白（）在帕金森病（PD）及相关路易体疾病（如帕金森病痴呆、路易体痴呆和多系统萎缩）的发病机制中起着核心作用。自1997年被发现为致病基因以来，α-突触核蛋白在蛋白质和基因层面一直是科学研究的重点。包括拷贝数变异、错义突变、短结构变异和单核苷酸多态性在内的突变可能导致PD，并影响蛋白质的构象变化，可能导致α-突触核蛋白及其异构体表达的改变，还可能影响不同组织和细胞类型中α-突触核蛋白在时间和空间水平上的调控。在理解α-突触核蛋白基因的生理转录和表观遗传调控以及转录调控的变化是否会导致PD及相关α-突触核蛋白病中的疾病和神经退行性变方面已经取得了很大进展。尽管这些神经退行性疾病的组织病理学变化相似，但它们在时间和空间上的表现及进展有所不同，这可能部分归因于α-突触核蛋白转录调控的改变或破坏。在本综述中，我们描述了导致PD和神经退行性疾病的不同基因改变，并在PD的发展背景下综述了α-突触核蛋白基因转录调控的各个方面。新技术、先进的基因工程和干细胞建模即将出现，以进一步阐明对基因调控过程的更好理解，并将其用于治疗开发。
