Department of Biochemistry, Faculty of Science, The MS University of Baroda, Vadodara, Gujarat, 390002, India.
Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
Mol Neurobiol. 2021 Apr;58(4):1819-1833. doi: 10.1007/s12035-020-02243-3. Epub 2021 Jan 6.
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，其特征是大脑黑质（SN）致密部的多巴胺能神经元进行性丧失。主要的病理标志包括α-突触核蛋白的细胞质包含物和线粒体功能障碍，除 SN 外，在中枢神经系统的其他部位也观察到这一点，这表明发病机制向旁观者神经元扩散。通过外泌体的神经元间通讯可能在疾病传播中起重要作用；然而，其机制尚不清楚。线粒体及其在与多泡体（MVB）和溶酶体的细胞器间通讯中的作用，以及在 PD 中调节外泌体释放的溶酶体作用尚未得到很好的理解。在本研究中，我们研究了线粒体-溶酶体通讯在神经元和神经胶质细胞中外泌体释放的调节作用。我们观察到 PD 应激导致多巴胺能神经元和神经胶质细胞中外泌体的释放增加。这些细胞中的 PD 应激状态显示出网络碎片化和线粒体功能障碍，这进一步导致溶酶体功能障碍，从而抑制自噬流。用雷帕霉素处理的神经元和神经胶质细胞显示出增强的自噬作用，并抑制外泌体的释放。结果表明，维持线粒体功能对于溶酶体功能和外泌体的释放很重要，这对于 PD 的发病机制很重要。
