RAC-alpha serine/threonine-protein kinase
response to growth factor
A growth-factor-activated lysosomal K<sup>+</sup> channel regulates Parkinson's pathology.
Lysosomes have fundamental physiological roles and have previously been implicated in Parkinson's disease<sup>1-5</sup>. However, how extracellular growth factors communicate with intracellular organelles to control lysosomal function is not well understood. Here we report a lysosomal K<sup>+</sup> channel complex that is activated by growth factors and gated by protein kinase B (AKT) that we term lysoK<sub>GF</sub>. LysoK<sub>GF</sub> 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<sub>GF</sub> 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<sub>GF</sub> 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.