Up-regulation of SNCA gene expression: implications to synucleinopathies.
Up-regulation of SNCA gene expression: implications to synucleinopathies.
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DOI：
10.1007/s10048-016-0478-0
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发表时间：
2016-07
期刊：
影响因子：
2.2
通讯作者：
Chiba-Falek O
中科院分区：
文献类型：
--
作者：
Tagliafierro L;Chiba-Falek O
突触核蛋白病是一组神经退行性疾病，其共有主要由α-突触核蛋白聚集体组成的细胞内蛋白包涵体的共同病理学病变。越来越多的证据，包括全基因组关联研究，暗示α-突触核蛋白（SNCA）基因在突触核蛋白病的病因学。然而，SNCA基因内导致帕金森病（PD）、路易体痴呆（DLB）、多系统萎缩（MSA）和其他突触核蛋白病的散发形式的精确变体及其作用的分子机制仍然难以捉摸。已经表明SNCA表达水平对于这些疾病的发展至关重要。在这里，我们回顾了几个模型系统，已开发出先进的SNCA表达水平的突触核蛋白病的病因学的作用的理解。我们还描述了不同的分子机制，调节SNCA基因的表达，并讨论了可能的策略，SNCA下调作为治疗方法的手段。最后，我们强调了一些例子，强调SNCA表达的遗传关联的结果和调节机制之间的关系，这表明，SNCA基因座的遗传变异是直接负责，至少部分地，基因表达的变化，并解释了SNCA与突触核蛋白病的报道协会。利用诱导多能干细胞（iPSC）衍生的神经元系和CRISPR/Cas9基因组编辑的未来研究将使我们能够验证，表征和操纵特定顺式遗传变体对SNCA表达的影响。此外，该模型系统将使我们能够比较不同的神经元和神经胶质细胞谱系参与突触核蛋白病代表一个有吸引力的策略，以阐明-共同和特定的SNCA -遗传变异，-监管机制，和-脆弱的表达水平潜在的突触核蛋白病谱系障碍。这一即将到来的知识将支持突触核蛋白病的精确医学的发展。
Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed by aggregates of alpha-synuclein protein. Accumulating evidence, including genome wide association studies, has implicated alpha-synuclein (SNCA) gene in the etiology of synucleinopathies. However, the precise variants within SNCA gene that contribute to the sporadic form of Parkinson's Diseases (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA) and other synucleinopathies, and their molecular mechanisms of action remain elusive. It has been suggested that SNCA expression levels are critical for the development of these diseases. Here we review several model systems that have been developed to advance the understanding of the role of SNCA expression levels in the etiology of synucleinopathies. We also describe different molecular mechanisms that regulate SNCA gene expression and discuss possible strategies for SNCA downregulation as means for therapeutic approaches. Finally, we highlight some examples that underscore the relationships between the genetic association findings and the regulatory mechanisms of SNCA expression, which suggest that genetic variability in SNCA locus is directly responsible, at least in part, to the changes in gene expression and explain the reported associations of SNCA with synucleinopathies. Future studies utilizing induced pluripotent stem cells (iPSCs)-derived neuronal lines and genome editing by CRISPR/Cas9, will allow us to validate, characterize, and manipulate the effects of particular cis-genetic variants on SNCA expression. Moreover, this model system will enable us to compare different neuronal and glia lineages involved in synucleinopathies representing an attractive strategy to elucidate – common and specific – SNCA -genetic variants, -regulatory mechanisms, and -vulnerable expression levels underlying synucleinopathy spectrum disorders. This forthcoming knowledge will support the development of precision medicine for synucleinopathies.