Department of Pathology and Environmental Health Sciences, The Geffen School of Medicine and School of Public Health, University of California, Los Angeles, 650 Charles E, Young Dr. S, CHS 71-295, Los Angeles, CA 90095, USA.
Mol Neurodegener. 2011 Dec 13;6:83. doi: 10.1186/1750-1326-6-83.
Alpha synuclein (SNCA) has been linked to neurodegenerative diseases (synucleinopathies) that include Parkinson's disease (PD). Although the primary neurodegeneration in PD involves nigrostriatal dopaminergic neurons, more extensive yet regionally selective neurodegeneration is observed in other synucleinopathies. Furthermore, SNCA is ubiquitously expressed in neurons and numerous neuronal systems are dysfunctional in PD. Therefore it is of interest to understand how overexpression of SNCA affects neuronal function in regions not directly targeted for neurodegeneration in PD.
The present study investigated the consequences of SNCA overexpression on cellular processes and functions in the striatum of mice overexpressing wild-type, human SNCA under the Thy1 promoter (Thy1-aSyn mice) by transcriptome analysis. The analysis revealed alterations in multiple biological processes in the striatum of Thy1-aSyn mice, including synaptic plasticity, signaling, transcription, apoptosis, and neurogenesis.
The results support a key role for SNCA in synaptic function and revealed an apoptotic signature in Thy1-aSyn mice, which together with specific alterations of neuroprotective genes suggest the activation of adaptive compensatory mechanisms that may protect striatal neurons in conditions of neuronal overexpression of SNCA.
α-突触核蛋白 (SNCA) 与包括帕金森病 (PD) 在内的神经退行性疾病 (突触核蛋白病) 有关。虽然 PD 中的主要神经退行性变涉及黑质纹状体多巴胺能神经元，但在其他突触核蛋白病中观察到更广泛但具有区域选择性的神经退行性变。此外，SNCA 在神经元中广泛表达，并且在 PD 中许多神经元系统功能失调。因此，了解 SNCA 的过表达如何影响 PD 中未直接针对神经退行性变的区域中的神经元功能是很有意义的。
本研究通过转录组分析，研究了在 Thy1 启动子（Thy1-aSyn 小鼠）下过表达野生型、人 SNCA 的小鼠纹状体中 SNCA 过表达对细胞过程和功能的影响。分析显示，Thy1-aSyn 小鼠纹状体中多个生物学过程发生改变，包括突触可塑性、信号转导、转录、细胞凋亡和神经发生。
这些结果支持 SNCA 在突触功能中的关键作用，并在 Thy1-aSyn 小鼠中揭示了一个细胞凋亡特征，这与神经保护基因的特定改变一起表明，在 SNCA 神经元过表达的情况下，激活适应性补偿机制可能会保护纹状体神经元。
