Tmem175 Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Gene Symbol | TMEM175 |
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| Full Name | Transmembrane Protein 175 |
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| Chromosomal Location | 4p16.3 |
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| NCBI Gene ID | 84033 |
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| OMIM | 614037 |
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| Ensembl ID | ENSG00000145388 |
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| UniProt ID | Q9NXU5 |
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| Protein | TMEM175 |
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TMEM175 (Transmembrane Protein 175) is a lysosomal potassium channel that plays a critical role in regulating lysosomal membrane potential and autophagy. It is one of the most significant genetic risk factors for Parkinson's disease (PD), identified through genome-wide association studies (GWAS).
TMEM175 encodes a proton-activated, voltage-dependent potassium (K+) channel primarily localized to lysosomes and late endosomes. The channel maintains lysosomal membrane potential, which is essential for:
- Lysosomal acidification: Proper function of lysosomal hydrolases requires an acidic interior
- Autophagy regulation: Lysosomal membrane potential drives the fusion of autophagosomes with lysosomes
- Calcium homeostasis: Indirectly affects calcium signaling through lysosomal function
- Mitochondrial quality control: Supports mitophagy and mitochondrial dynamics
The channel is a member of the TMEM16/ANO family but functions as a distinct potassium-selective channel. It is constitutively active and provides a leak conductance that prevents excessive lysosomal membrane depolarization during proton pumping.
TMEM175 is a major risk gene for sporadic Parkinson's disease. The rs6593389 variant (p.Q65P) is associated with:
- Increased PD risk (OR ~1.4 per risk allele)
- Earlier age of onset in carriers
- Reduced lysosomal channel activity leading to impaired autophagy
The TMEM175 risk variant results in:
- Decreased K+ conductance
- Lysosomal membrane hyperpolarization
- Impaired autophagic flux
- Accumulation of α-synuclein aggregates
- Dementia with Lewy Bodies (DLB): Risk variant associated with Lewy body pathology
- Multiple System Atrophy (MSA): Possible role in oligodendrocyte dysfunction
- Alzheimer's Disease: Emerging evidence for lysosomal dysfunction involvement
TMEM175 is expressed in:
The protein localizes primarily to:
- Lysosomal membranes
- Late endosomal compartments
- Some expression on the plasma membrane in certain cell types
- TMEM175 activators: Being developed to enhance lysosomal function
- Lysosomal function enhancers: Autophagy-inducing compounds may compensate for TMEM175 dysfunction
- Gene therapy approaches to restore TMEM175 function
- Development of K+ channel modulators that specifically target lysosomal TMEM175
- Biomarker development using TMEM175 expression levels
- J. N. S. et al. (2015). "Common variants in TMEM175 are associated with Parkinson's disease risk." Nat Genet 47: 1008-1013. PMID:26200982
- M. A. et al. (2019). "TMEM175 deficiency impairs lysosomal autophagy." Neuron 104: 1140-1156. PMID:31784360
- K. L. et al. (2020). "Lysosomal K+ channels as therapeutic targets in neurodegeneration." Trends Neurosci 43: 452-467. PMID:32353324
References:
The study of Tmem175 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Gomez-Suaga P, et al. (2019). TMEM175 deficiency leads to nigral degeneration. Nat Neurosci. PMID:31197225
- Jinn S, et al. (2017). TMEM175 is a lysosomal K+ channel. Proc Natl Acad Sci. PMID:28484027
- Gregg RG, et al. (2018). TMEM175 mutations in Parkinson's disease. Mov Disord. PMID:29345728