How strong is the evidence that Parkinson's disease is a prion disorder?
How strong is the evidence that Parkinson's disease is a prion disorder?
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DOI：
10.1097/wco.0000000000000349
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发表时间：
2016-08
影响因子：
4.8
通讯作者：
Kordower JH
中科院分区：
文献类型：
--
作者：
Brundin P;Ma J;Kordower JH
我们描述了支持α-突触核蛋白在帕金森病和相关α-突触核蛋白病中具有朊病毒样作用的假设的证据，并讨论了这种新思维如何影响诊断和疾病修饰疗法的发展。观察到移植到帕金森氏病患者体内的未成熟多巴胺神经元可以形成路易体，这引发了人们对α-突触核蛋白假定的朊病毒样特性的兴趣。我们叙述了证实错误折叠的α-突触核蛋白可以表现出疾病传播特性的实验结果，并描述了它们如何与α-突触核蛋白病中α-突触核蛋白聚集体的传播有关。我们分享对潜在分子机制及其与新治疗靶点的相关性的见解。最后，我们讨论了α-突触核蛋白错误折叠的初始触发因素可能是什么，错误折叠事件可能发生在身体的何处，以及这如何指导新诊断工具的开发。我们推测，解剖触发位点的差异和α-突触核蛋白纤维结构的变异性可能有助于α-突触核蛋白病之间的临床差异。认识到α-突触核蛋白病理学可以在神经退行性疾病的脑区域之间传播，加深和扩大了我们对潜在致病过程的理解，这可以导致开发新的诊断工具以及识别新的治疗靶点。
We describe evidence supporting the hypothesis that α-synuclein has a prion-like role in Parkinson’s disease and related α-synucleinopathies, and discuss how this novel thinking impacts the development of diagnostics and disease-modifying therapies. Observations that immature dopamine neurons grafted to Parkinson’s disease patients can develop Lewy bodies triggered a surge of interest in the putative prion-like properties of α-synuclein. We recount results from experiments which confirm that misfolded α-synuclein can exhibit disease-propagating properties, and describe how they relate to the spreading of α-synuclein aggregates in α-synucleinopathies. We share insights into the underlying molecular mechanisms and their relevance to novel therapeutic targets. Finally, we discuss what the initial triggers of α-synuclein misfolding might be, where in the body the misfolding events might take place and how this can instruct development of novel diagnostic tools. We speculate that differences in anatomical trigger sites and variability in α-synuclein fibril structure can contribute to clinical differences between α-synucleinopathies. The realization that α-synuclein pathology can propagate between brain regions in neurodegenerative diseases has deepened and expanded our understanding of potential pathogenic processes which can lead to the development of novel diagnostic tools as well as the identification of new therapeutic targets.