Nat Commun：散发性帕金森氏病的发病机制

近日，哥伦比亚大学医学中心（CUMC）托布研究所研究人员发现了常见的散发性帕金森氏症形式的发病机制，这一发现揭示了治疗该疾病的潜在新的治疗靶点。研究结果主要是分析人脑组织后得出的，相关研究论文发表在Nature Communications杂志上。

研究一种罕见的家族性（遗传）帕金森氏形式发现一种称为α-突触核蛋白的蛋白质在疾病的发生发展中起到了重要作用。那些α-突触核蛋白基因存在额外拷贝数量的患者，会产生过量的α-突触核蛋白，后者可以破坏神经元。影响最明显的是多巴胺神经元，多巴胺神经元主要控制正常机体运动。帕金森氏症的另一个重要特点是过剩的α-突触核蛋白主要在大脑中聚集。
 
由于绝大多数帕金森病患者没有携带该罕见遗传性基因突变，所以一个关键的问题是为什么这些常见散发性帕金森氏患者仍然存在多余的α-s突触核蛋白质。博士Abeli​ovich说：该研究中一个突破点就是主要根据实际病人组织而不是仅仅动物模型来详细分析研究。事实上，较长形式的α-突触核蛋白是人类特有的，该蛋白基因的变异与疾病密切相关。

Abeli ovich博士说：此外，我们发现帕金森氏患者暴露在毒素环境下后，可以增加这种较长形式的α-突触核蛋白的数量，因此，上述问题的机制可能是由遗传和环境因素共同影响的。

研究结果表明那些可以降低大脑中的细长α-突触核蛋白积累的药物可能对帕金森氏有治疗价值。CUMC的团队目前正在寻找候选药物，这项研究是由Michael J. Fox基金会、美国国立卫生研究院、国家神经疾病研究所等资助。

doi:10.1038/ncomms2032
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Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology

Herve Rhinn,Liang Qiang,Toru Yamashita,David Rhee,Ari Zolin,William Vanti& Asa Abeliovich

α-Synuclein is implicated both in physiological functions at neuronal synaptic terminals as well as in pathological processes in the context of Parkinson's disease. However, the molecular mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of α-synuclein with an extended 3′ untranslated region, termed aSynL, appear selectively linked to pathological processes, relative to shorter α-synuclein transcripts. Common variants in the aSynL 3′ untranslated region associated with Parkinson's disease risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation site selection. We demonstrate that the presence of the extended aSynL transcript 3′ untranslated region impacts accumulation of α-synuclein protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of Parkinson's disease pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of Parkinson's disease-associated genetic and environmental variations.