A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology

• Published in: Nature (London) Vol. 591; no. 7850; pp. 431 - 437
• Main Authors: Wie, Jinhong, Liu, Zhenjiang, Song, Haikun, Tropea, Thomas F., Yang, Lu, Wang, Huanhuan, Liang, Yuling, Cang, Chunlei, Aranda, Kimberly, Lohmann, Joey, Yang, Jing, Lu, Boxun, Chen-Plotkin, Alice S., Luk, Kelvin C., Ren, Dejian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.03.2021; Nature Publishing Group
• Subjects: 14; 631/378/1689/1718; 631/378/2586; 631/80/86/2372; 9/74; 96/95; AKT protein; Alleles; alpha-Synuclein - metabolism; Amino acids; Animals; Biocatalysis; Brain-derived neurotrophic factor; Catalysis; Catalytic activity; Damage accumulation; Dopaminergic Neurons - metabolism; Female; Gain of Function Mutation; Growth factors; HEK293 Cells; Humanities and Social Sciences; Humans; Insulin; Intercellular Signaling Peptides and Proteins - metabolism; Intracellular; Kinases; Loss of Function Mutation; Lysosomes; Lysosomes - metabolism; Male; Mice; Mice, Knockout; Motor Skills; Movement disorders; multidisciplinary; Multiprotein Complexes - chemistry; Multiprotein Complexes - deficiency; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Neurodegenerative diseases; Neurons; Organelles; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Physiological effects; Pore formation; Potassium - metabolism; Potassium channels; Potassium Channels - chemistry; Potassium Channels - deficiency; Potassium Channels - genetics; Potassium Channels - metabolism; Protein Binding; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Risk; Science; Science (multidisciplinary); Synuclein
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-021-03185-z

Lysosomes have fundamental physiological roles and have previously been implicated in Parkinson’s disease 1 – 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. The identification of a lysosomal K + channel complex—comprising AKT and the pore-forming TMEM175—provides insights into the mechanisms through which variants of the pore-forming protein affect the development of Parkinson’s disease.