Lysosomes have fundamental physiological roles and have previously been implicated in Parkinson’s disease^1,2,3,4,5. However, how extracellular growth factors communicate with intracellular organelles to control lysosomal function is not well understood. Here we report a lysosomal K⁺ channel complex that is activated by growth factors and gated by protein kinase B (AKT) that we term lysoK_GF. LysoK_GF consists of a pore-forming protein TMEM175 and AKT: TMEM175 is opened by conformational changes in, but not the catalytic activity of, AKT. The minor allele at rs34311866, a common variant in TMEM175, is associated with an increased risk of developing Parkinson’s disease and reduces channel currents. Reduction in lysoK_GF function predisposes neurons to stress-induced damage and accelerates the accumulation of pathological α-synuclein. By contrast, the minor allele at rs3488217—another common variant of TMEM175, which is associated with a decreased risk of developing Parkinson’s disease—produces a gain-of-function in lysoK_GF during cell starvation, and enables neuronal resistance to damage. Deficiency in TMEM175 leads to a loss of dopaminergic neurons and impairment in motor function in mice, and a TMEM175 loss-of-function variant is nominally associated with accelerated rates of cognitive and motor decline in humans with Parkinson’s disease. Together, our studies uncover a pathway by which extracellular growth factors regulate intracellular organelle function, and establish a targetable mechanism by which common variants of TMEM175 confer risk for Parkinson’s disease.

溶酶体具有基本的生理作用，以前曾与帕金森病^1,2,3,4,5有牵连。然而，细胞外生长因子如何与细胞内细胞器交流以控制溶酶体功能尚不清楚。在这里，我们报告了一种溶酶体 K ⁺通道复合物，它由生长因子激活并由我们称之为 lysoK _GF的蛋白激酶 B (AKT) 门控。LysoK _GF由成孔蛋白 TMEM175 和 AKT 组成：TMEM175 通过 AKT 的构象变化而不是催化活性打开。rs34311866 的次要等位基因，TMEM175 中的常见变体，与患帕金森病的风险增加有关，并减少通道电流。lysoK _GF功能的降低使神经元易受压力诱导的损伤并加速病理性 α-突触核蛋白的积累。相比之下，rs3488217 的次要等位基因——TMEM175 的另一个常见变体，与帕金森病发病风险降低有关——在细胞饥饿期间产生 lysoK _GF的功能增益，并使神经元能够抵抗损伤。TMEM175 缺乏会导致小鼠多巴胺能神经元丧失和运动功能受损，而TMEM175功能丧失变体名义上与帕金森病患者认知和运动能力下降的速度加快有关。总之，我们的研究揭示了细胞外生长因子调节细胞内细胞器功能的途径，并建立了TMEM175的常见变体赋予帕金森病风险的靶向机制。