Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal aging

Parkinson’s disease is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and intraneuronal accumulation of α-synuclein (αSyn) protein. Age is the biggest risk factor for Parkinson’s and has been suggested to create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that aging leads to increased αSyn expression in DA neurons and it is possible that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To investigate this, adult female Sprague-Dawley rats received unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration. Furthermore, SKOR1 impaired neurite growth to the same extent as α-synuclein, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuron survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent to which αSyn upregulates SKOR1 may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which age-related changes may influence molecular mechanisms controlling neuronal integrity across the lifespan.帕金森病（Parkinson’s disease）以黑质（substantia nigra, SN）内多巴胺能（dopaminergic, DA）神经元进行性丢失以及神经元内α-突触核蛋白（α-synuclein, αSyn）聚集为特征。年龄是帕金森病最主要的危险因素，且被认为可诱导易感的帕金森前驱状态，但二者关联的驱动机制尚不明确。已知衰老会导致多巴胺能神经元内αSyn表达上调，这可能改变维持黑质纹状体完整性的核心分子过程。为探究该机制，研究人员对成年雌性斯普拉格-道利大鼠（Sprague-Dawley rats）实施单侧黑质内注射，分别注射携带野生型人源αSyn的腺相关病毒（adeno-associated viral, AAV）载体（AAV-αSyn）与对照载体（AAV-Null）。术后20周时，AAV-αSyn未对运动行为产生不良影响，但在中脑及同侧纹状体中均检测到人源野生型αSyn的表达。基因芯片分析显示，在AAV-αSyn组的同侧黑质中，上调幅度最高的基因为SKI家族转录共抑制因子1（SKI Family Transcriptional Corepressor 1, SKOR1）。线粒体功能生物能量状态分析表明，SKOR1过表达会降低细胞呼吸最大速率。此外，SKOR1对神经突生长的损伤程度与α-突触核蛋白相当，且可抑制骨形态发生蛋白-SMAD依赖性转录——该通路可促进多巴胺能神经元存活与生长。鉴于人体黑质中衰老对多巴胺能神经元丢失的常规影响，αSyn上调SKOR1的程度可能决定个体是经历正常的黑质纹状体衰老，还是达到前驱期帕金森病的发病阈值。该研究为理解衰老相关变化如何影响贯穿生命周期的神经元完整性调控分子机制提供了全新视角。