Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta region of the brain. The main pathological hallmark involves cytoplasmic inclusions of α-synuclein and mitochondrial dysfunction, which is observed in other part of the central nervous system other than SN suggesting the spread of pathogenesis to bystander neurons. The inter-neuronal communication through exosomes may play an important role in the spread of the disease; however, the mechanisms are not well elucidated. Mitochondria and its role in inter-organellar crosstalk with multivesicular body (MVB) and lysosome and its role in modulation of exosome release in PD is not well understood. In the current study, we investigated the mitochondria-lysosome crosstalk modulating the exosome release in neuronal and glial cells. We observed that PD stress showed enhanced release of exosomes in dopaminergic neurons and glial cells. The PD stress condition in these cells showed fragmented network and mitochondrial dysfunction which further leads to functional deficit of lysosomes and hence inhibition of autophagy flux. Neuronal and glial cells treated with rapamycin showed enhanced autophagy and inhibited the exosomal release. The results here suggest that maintenance of mitochondrial function is important for the lysosomal function and hence exosomal release which is important for the pathogenesis of PD.

帕金森病 (PD) 是一种神经退行性疾病，其特征是大脑的黑质 (SN) 致密部区域中的多巴胺能神经元进行性丧失。主要病理标志涉及 α-突触核蛋白的细胞质内含物和线粒体功能障碍，这在 SN 以外的中枢神经系统的其他部分观察到，表明发病机制已扩散到旁观者神经元。通过外泌体的神经元间通讯可能在疾病的传播中起重要作用；然而，其机制尚未得到很好的阐明。线粒体及其在与多泡体 (MVB) 和溶酶体的细胞器间串扰中的作用及其在 PD 中调节外泌体释放中的作用尚不清楚。在目前的研究中，我们研究了调节神经元和神经胶质细胞外泌体释放的线粒体-溶酶体串扰。我们观察到 PD 应激显示多巴胺能神经元和神经胶质细胞中外泌体的释放增强。这些细胞中的 PD 应激条件显示出破碎的网络和线粒体功能障碍，这进一步导致溶酶体的功能缺陷，从而抑制自噬通量。用雷帕霉素处理的神经元和神经胶质细胞显示出自噬增强并抑制外泌体释放。这里的结果表明，线粒体功能的维持对于溶酶体功能很重要，因此外泌体的释放对于 PD 的发病机制很重要。这些细胞中的 PD 应激条件显示出破碎的网络和线粒体功能障碍，这进一步导致溶酶体的功能缺陷，从而抑制自噬通量。用雷帕霉素处理的神经元和神经胶质细胞显示出自噬增强并抑制外泌体释放。这里的结果表明，线粒体功能的维持对于溶酶体功能很重要，因此外泌体的释放对于 PD 的发病机制很重要。这些细胞中的 PD 应激条件显示出破碎的网络和线粒体功能障碍，这进一步导致溶酶体的功能缺陷，从而抑制自噬通量。用雷帕霉素处理的神经元和神经胶质细胞显示出自噬增强并抑制外泌体释放。这里的结果表明，线粒体功能的维持对于溶酶体功能很重要，因此外泌体的释放对于 PD 的发病机制很重要。