Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson's disease
Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson's disease
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DOI：
10.1007/s00401-018-1892-1
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发表时间：
2018-10-01
影响因子：
12.7
通讯作者：
Bellucci, Arianna
中科院分区：
文献类型：
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作者：
Faustini, Gaia;Longhena, Francesca;Bellucci, Arianna
帕金森病（PD）是最常见的神经退行性运动障碍，其特征是黑质多巴胺神经元的逐渐丧失。路易小体（LB）中原纤维聚集α -突触核蛋白的沉积被认为在疾病中起致病作用，是PD的另一个关键的神经病理学标志。我们最近报道了突触蛋白III (Syn III)，一种与α -突触核蛋白协同调节多巴胺释放的突触磷酸化蛋白，存在于构成PD患者LB的α -突触核蛋白不溶性原纤维中。此外，我们观察到Syn III基因的沉默可以在体外阻止α -突触核蛋白原纤维聚集。这一证据表明Syn III可能在α -突触核蛋白病理沉积中起关键作用。为了验证这一假设，我们研究了单侧注射腺相关病毒载体（AAV）介导的人类野生型(wt) α -突触核蛋白过表达（AAV-h α Syn）是否可以保护小鼠Syn III敲除（ko）免受α -突触核蛋白聚集和黑质纹状体神经元变性的影响。我们发现注射AAV-h α - Syn的Syn III小鼠没有形成纤维不溶性α -突触核蛋白聚集体，通过原位接近结扎试验（PLA）检测到的α -突触核蛋白低聚物数量减少，ser129磷酸化的α -突触核蛋白水平降低。此外，注射AAV-h α Syn可保护Syn III小鼠黑质纹状体神经元免受突触损伤和变性的影响。我们的观察结果表明，Syn III是α -突触核蛋白聚集和毒性的重要介质，并确定Syn III是PD的新治疗靶点。
Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of nigral dopamine neurons. The deposition of fibrillary aggregated alpha-synuclein in Lewy bodies (LB), that is considered to play a causative role in the disease, constitutes another key neuropathological hallmark of PD. We have recently described that synapsin III (Syn III), a synaptic phosphoprotein that regulates dopamine release in cooperation with alpha-synuclein, is present in the alpha-synuclein insoluble fibrils composing the LB of patients affected by PD. Moreover, we observed that silencing of Syn III gene could prevent alpha-synuclein fibrillary aggregation in vitro. This evidence suggests that Syn III might be crucially involved in alpha-synuclein pathological deposition. To test this hypothesis, we studied whether mice knock-out (ko) for Syn III might be protected from alpha-synuclein aggregation and nigrostriatal neuron degeneration resulting from the unilateral injection of adeno-associated viral vectors (AAV)-mediating human wild-type (wt) alpha-synuclein overexpression (AAV-h alpha syn). We found that Syn III ko mice injected with AAV-h alpha syn did not develop fibrillary insoluble alpha-synuclein aggregates, showed reduced amount of alpha-synuclein oligomers detected by in situ proximity ligation assay (PLA) and lower levels of Ser129-phosphorylated alpha-synuclein. Moreover, the nigrostriatal neurons of Syn III ko mice were protected from both synaptic damage and degeneration triggered by the AAV-h alpha syn injection. Our observations indicate that Syn III constitutes a crucial mediator of alpha-synuclein aggregation and toxicity and identify Syn III as a novel therapeutic target for PD.