Loss of functional alpha-synuclein: a toxic event in Parkinson's disease?
Loss of functional alpha-synuclein: a toxic event in Parkinson's disease?
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DOI：
10.3233/jpd-012138
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Manfredsson FP
中科院分区：
文献类型：
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作者：
Kanaan NM;Manfredsson FP
发现α-突触核蛋白（α-syn）是帕金森病（PD）神经病理学标志的主要成分，并在许多遗传形式的PD中鉴定出α-syn突变，这使α-syn成为PD发病机制中重要因素之首。基于α-syn在患者脑中的病理性积累，该领域目前专注于旨在减少或消除α-syn的治疗策略。然而，最近的证据表明α-syn是神经元（即多巴胺神经元）存活的关键蛋白质，并且维持一定水平的生物功能性α-syn是靶向α-syn治疗的重要考虑因素。尽管对α-syn的广泛兴趣，正常的生物学功能仍然难以捉摸，但大量的工作都集中在解决这个问题上。本文就α-syn的功能、α-syn的折叠和聚集以及α-syn在疾病中的作用进行综述。最后，我们将提出一个关于PD发病机制的相对新颖的假说，该假说基于以下前提：功能性α-syn对细胞存活至关重要，生物学功能性α-syn的减少，无论是通过聚集还是表达减少，都可能导致PD的神经退行性变。
The discovery that alpha-synuclein (α-syn) is the primary component of the neuropathological hallmarks of Parkinson’s disease (PD) and the identification of α-syn mutations in numerous inherited forms of PD has positioned α-syn at the top of the list of important factors in the pathogenesis of PD. Based on the pathological accumulation of α-syn in the brains of patients, the field is currently focused on therapeutic strategies that aim to reduce or eliminate α-syn. However, recent evidence suggests α-syn is a critical protein in neuron (i.e. dopamine neurons) survival and that maintaining a certain level of biologically functional α-syn is an important consideration in targeting α-syn for therapies. Despite the widespread interest in α-syn, the normal biological functions remain elusive, but a large body of work is focused on addressing this issue. In this review, we will discuss the current evidence related to α-syn function, α-syn folding and aggregation, and α-syn’s role in disease. Finally, we will propose a relatively novel hypothesis on the pathogenesis of PD that hinges upon the premises that functional α-syn is critical to cell survival and that a reduction in biologically functional α-syn, whether through aggregation or reduced expression, may lead to the neurodegeneration in PD.