α-突触核蛋白与神经元内血红蛋白相互作用对多巴胺神经元线粒体功能的影响

The abnormal expression and aggregation of α-synuclein (α-Syn) has been shown to be the major contributor to the degeneration of dopaminergic (DA) neurons in Parkinson’s disease (PD). However, the underlying mechanism remains elusive. We have previously found that α-Syn can bind to peripheral red blood cell hemoglobin (pHb), forming a pHb-α-Syn complex, which is significantly increased in PD patients. We have further identified that α-Syn can also bind to neuronal hemoglobin (nHb), forming a nHb-α-Syn complex, which is also dramatically increased in the brains of PD animals. We therefore hypothesize that the formation of nHb-α-Syn complex in DA neurons will impair the function of mitochondria, leading to degeneration of DA neurons, due to the pivotal role of nHb in maintaining the homeostasis of neuronal mitochondria. In the proposed project, primary neuronal cultures as well as the brain samples from PD patients and PD animals will be used to study the mechanisms for the formation of nHb-α-Syn complex and the effects of nHb-α-Syn complex on mitochondrial function and mitochondria-mediated apoptosis in DA neurons. In addition, the correlation between alterations in levels of nHb-α-Syn complex and pHb-α-Syn complex will be analyzed. The study will deepen our understanding of the mechanisms for the degeneration of DA neurons in PD.

α-突触核蛋白（α-Syn）的异常表达和聚集是引起帕金森病（PD）人黑质多巴胺（DA）神经元退变的重要原因，但其机制尚未完全阐明。我们发现，α-Syn可以与外周血红细胞内的血红蛋白（pHb）结合成复合物，与pHb结合的α-Syn（pHb-α-Syn）含量在PD病人明显增高；此外，α-Syn 也可以与神经元内的血红蛋白（nHb）结合形成复合物，并且nHb-α-Syn含量在PD模型动物脑组织中也显著增加。由于nHb在维持线粒体稳态的重要作用，nHb-α-Syn复合物的形成将减少游离nHb含量，从而损害线粒体功能。本项目拟利用PD病人和动物样本，研究nHb-α-Syn复合物形成的机制及其对线粒体功能及DA神经元凋亡的影响；分析nHb-α-Syn含量变化与外周血pHb-α-Syn含量变化的相关性。该项研究将加深我们对PD病人DA神经元退变机制的了解。

α-突触核蛋白（α-Syn）的异常表达和聚集是引起帕金森病（PD）人黑质多巴胺（DA）神经元退变的重要原因，但其机制尚未完全阐明。我们发现，α-Syn可以与外周血红细胞内的血红蛋白（peripheral hemoglobin，pHb）结合成复合物，与pHb结合的α-Syn（pHb-α-Syn）含量在PD病人明显增高。我们在本项目中进一步证明，α-Syn 也可以与神经元内的血红蛋白（neuronal hemoglobin，nHb）结合形成复合物（nHb-α-Syn），在老化猴模型证明，随着纹状体局部α-Syn 增加，细胞浆中的nHb-α-Syn 含量也随之增加，而线粒体组分的nHb-α-Syn 则减少，而在α-Syn增龄性变化不明显的小脑，胞浆和线粒体组分中的nHb-α-Syn含量变化不显著。我们进一步在细胞水平证明，nHb-α-Syn复合物形成通过降低线粒体游离nHb而导致线粒体呼吸链复合酶I活性下降。这一发现部分解释了帕金森病人线粒体呼吸链复合酶I缺陷的原因。此外，我们证明，pHb-α-Syn 含量与中枢胞浆nHb-α-Syn呈正相关，而与线粒体中的nHb-α-Syn 含量呈负相关。鉴于pHb-α-Syn 变化在PD诊断具有较高的特异性和敏感性，这种相关性为pHb-α-Syn改变 的病理意义提供了有价值的证据。