Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Nat Commun. 2021 Mar 22;12(1):1807. doi: 10.1038/s41467-021-22113-3.
Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. In this study, we demonstrate that mitochondria-lysosome contacts can dynamically form in the soma, axons, and dendrites of human neurons, allowing for their bidirectional crosstalk. Parkinson's disease patient derived neurons harboring mutant GBA1 exhibited prolonged mitochondria-lysosome contacts due to defective modulation of the untethering protein TBC1D15, which mediates Rab7 GTP hydrolysis for contact untethering. This dysregulation was due to decreased GBA1 (β-glucocerebrosidase (GCase)) lysosomal enzyme activity in patient derived neurons, and could be rescued by increasing enzyme activity with a GCase modulator. These defects resulted in disrupted mitochondrial distribution and function, and could be further rescued by TBC1D15 in Parkinson's patient derived GBA1-linked neurons. Together, our work demonstrates a potential role of mitochondria-lysosome contacts as an upstream regulator of mitochondrial function and dynamics in midbrain dopaminergic neurons in GBA1-linked Parkinson's disease.
线粒体-溶酶体接触点最近被鉴定为介导这两种细胞器之间串扰的部位，但它们在正常和患病人类神经元中的作用尚不清楚。在这项研究中，我们证明了线粒体-溶酶体接触点可以在人类神经元的体部、轴突和树突中动态形成，允许它们进行双向串扰。携带突变 GBA1 的帕金森病患者来源的神经元由于无束缚蛋白 TBC1D15 的调节缺陷而表现出延长的线粒体-溶酶体接触点，TBC1D15 介导 Rab7 GTP 水解以解除接触。这种失调是由于患者来源的神经元中 GBA1（β-葡糖脑苷脂酶 (GCase)）溶酶体酶活性降低引起的，可通过增加 GCase 调节剂来恢复酶活性。这些缺陷导致线粒体分布和功能紊乱，在帕金森病患者来源的与 GBA1 相关的神经元中，TBC1D15 可进一步挽救这些缺陷。总之，我们的工作表明线粒体-溶酶体接触点作为 GBA1 相关帕金森病中中脑多巴胺能神经元中线粒体功能和动力学的上游调节剂的潜在作用。
