The usual suspects, dopamine and alpha-synuclein, conspire to cause neurodegeneration
The usual suspects, dopamine and alpha-synuclein, conspire to cause neurodegeneration
复制标题
DOI：
10.1002/mds.27607
复制
发表时间：
2019-02-01
影响因子：
8.6
通讯作者：
Ischiropoulos, Harry
中科院分区：
文献类型：
--
作者：
Mor, Danielle E.;Daniels, Malcolm J.;Ischiropoulos, Harry
帕金森病（PD）主要是由黑质（SN）中产生多巴胺的神经元的损失驱动的运动障碍。多巴胺的氧化特性的早期鉴定暗示它是PD中氧化应激的潜在来源，但很少有研究调查体内多巴胺神经毒性。在PD的标志性路易体病理学中发现导致PD的α-突触核蛋白突变和聚集的α-突触核蛋白的存在揭示了另一个重要的参与者。尽管广泛的努力，α-突触核蛋白聚集在神经变性中的确切作用仍然不清楚。我们最近操纵了老年小鼠的多巴胺水平和α-突触核蛋白表达，发现只有这两个因素的结合才能引起SN的进行性神经变性和相关的运动缺陷。多巴胺修饰的α-突触核蛋白在SN中聚集，导致α-突触核蛋白寡聚体的更大丰度和独特的多巴胺诱导的寡聚体构象。此外，多巴胺-α-突触核蛋白相互作用的破坏拯救了转基因秀丽隐杆线虫模型中的多巴胺能神经元免于变性。在这个角度来看，我们讨论了已知的α-突触核蛋白和多巴胺生物学的背景下，这些发现，审查α-突触核蛋白寡聚体毒性和潜在的机制的证据，并讨论治疗的意义。(c)2019国际帕金森和运动障碍协会
Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine-producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD-causing mutations in alpha-synuclein and the presence of aggregated alpha-synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of alpha-synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and alpha-synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified alpha-synuclein aggregation in the SN, resulting in greater abundance of alpha-synuclein oligomers and unique dopamine-induced oligomeric conformations. Furthermore, disruption of the dopamine-alpha-synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known alpha-synuclein and dopamine biology, review the evidence for alpha-synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. (c) 2019 International Parkinson and Movement Disorder Society