Accumulation of α-synuclein aggregates in the substantia nigra pars compacta is central in the pathophysiology of Parkinson’s disease, leading to the degeneration of dopaminergic neurons and the manifestation of motor symptoms. Although several PD models mimic the pathological accumulation of α-synuclein after overexpression, they do not allow for controlling and monitoring its aggregation. We recently generated a new optogenetic tool by which we can spatiotemporally control the aggregation of α-synuclein using a light-induced protein aggregation system. Using this innovative tool, we aimed to characterize the impact of α-synuclein clustering on mitochondria, whose activity is crucial to maintain neuronal survival. We observed that aggregates of α-synuclein transiently and dynamically interact with mitochondria, leading to mitochondrial depolarization, lower ATP production, mitochondrial fragmentation and degradation via cardiolipin externalization-dependent mitophagy. Aggregation of α-synuclein also leads to lower mitochondrial content in human dopaminergic neurons and in mouse midbrain. Interestingly, overexpression of α-synuclein alone did not induce mitochondrial degradation. This work is among the first to clearly discriminate between the impact of α-synuclein overexpression and aggregation on mitochondria. This study thus represents a new framework to characterize the role of mitochondria in PD.

黑质致密部中 α-突触核蛋白聚集体的积累是帕金森病病理生理学的核心，导致多巴胺能神经元变性和运动症状的表现。尽管一些 PD 模型模拟了 α-突触核蛋白过度表达后的病理积累，但它们不允许控制和监测其聚集。我们最近开发了一种新的光遗传学工具，通过它我们可以使用光诱导的蛋白质聚集系统时空控制 α-突触核蛋白的聚集。使用这种创新工具，我们旨在表征 α-突触核蛋白聚集对线粒体的影响，线粒体的活性对于维持神经元存活至关重要。我们观察到，α-突触核蛋白的聚集体与线粒体瞬时、动态地相互作用，导致线粒体去极化、ATP 产量降低、线粒体碎片和通过心磷脂外化依赖性线粒体自噬降解。α-突触核蛋白的聚集还会导致人类多巴胺能神经元和小鼠中脑中线粒体含量降低。有趣的是，单独过度表达 α-突触核蛋白并不会诱导线粒体降解。这项工作是第一个明确区分 α-突触核蛋白过度表达和聚集对线粒体的影响的工作。因此，这项研究代表了一个表征线粒体在帕金森病中作用的新框架。