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A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology
Open accessAbstract
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.
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“Second, active cathepsin B can leak into the cytoplasm after lysosomal membrane permeabilization (LMP) in contexts where lysosomal membrane integrity is compromised, such as upon lysosomal deacidification44,69.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [69]
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Genetics and Pathogenesis of Parkinson's Syndrome
Ye, H., Robak, L. A., Yu, M., Cykowski, M. D., & Shulman, J. M. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-031521-034145 · Cited by 503
Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases
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Energy metabolism in health and diseases
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Self-citationParkinson’s disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes
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Lysosomal dysfunction in neurodegeneration: emerging concepts and methods
Udayar, V., Chen, Y., Sidransky, E., & Jagasia, R. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2021.12.004 · Cited by 255
Metadata
- Authors
- Wie, J., Liu, Z., Song, H., Tropea, T. F., Yang, L., Wang, H., Liang, Y., Cang, C., Aranda, K., Lohmann, J., Yang, J., Lu, B., Chen-Plotkin, A. S., Luk, K. C., & Ren, D.
- Affiliations
- University of Pennsylvania (US)
- Fudan University (CN)
- Peking University (CN)
- Corresponding author
- Luk, Kelvin C.
- Ren, Dejian
- ORCID
- Venue
- Nature
- Published
- 2021-01-27
- Volume
- 591
- Issue
- 7850
- Pages
- 431-437
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7979525
- OpenAlex
- W3124663999
- Cited by
- 120
- References
- 89
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 22 · 2023: 27 · 2022: 19 · 2021: 11
- FWCI
- 9.45
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-03-31)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (U19AG062418)
- National Heart, Lung, and Blood Institute (R01HL147379)
- National Cancer Institute (P30CA016520)
- National Institute of General Medical Sciences (R01GM133172)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK019525, P30DK050306)
- National Institute of Neurological Disorders and Stroke (K23NS114167, P50NS053488, R01NS115139, R01NS088322)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- Parkinson's disease, TMEM175, Akt, growth factor signaling, lysosomes, alpha-synuclein aggregation, dopaminergic neurons, genetic variants, neuronal stress, cell starvation, motor function
- MeSH terms
- Loss of Function Mutation, Gain of Function Mutation, Animals, Female, Humans, Lysosomes, Male, Motor Skills, Parkinson Disease, Potassium, Protein Binding, Potassium Channels, Mice, Knockout, Intercellular Signaling Peptides and Proteins, Multiprotein Complexes, Proto-Oncogene Proteins c-akt, Mice, alpha-Synuclein, Biocatalysis, HEK293 Cells, Dopaminergic Neurons
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