TMEM175 Gene
Introduction
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.
<div class="infobox infobox-gene">
<table>
<tr><th>Gene Symbol</th><td><strong>TMEM175</strong></td></tr>
<tr><th>Full Name</th><td>Transmembrane Protein 175</td></tr>
<tr><th>Chromosomal Location</th><td>4p16.3</td></tr>
<tr><th>NCBI Gene ID</th><td>84033</td></tr>
<tr><th>OMIM</th><td>614037</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000145388</td></tr>
<tr><th>UniProt ID</th><td>Q9NXU5</td></tr>
<tr><th>Protein</th><td>TMEM175</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">87 edges</a></td>
</tr>
</table>
</div>
Overview
...TMEM175 Gene
Introduction
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.
<div class="infobox infobox-gene">
<table>
<tr><th>Gene Symbol</th><td><strong>TMEM175</strong></td></tr>
<tr><th>Full Name</th><td>Transmembrane Protein 175</td></tr>
<tr><th>Chromosomal Location</th><td>4p16.3</td></tr>
<tr><th>NCBI Gene ID</th><td>84033</td></tr>
<tr><th>OMIM</th><td>614037</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000145388</td></tr>
<tr><th>UniProt ID</th><td>Q9NXU5</td></tr>
<tr><th>Protein</th><td>TMEM175</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">87 edges</a></td>
</tr>
</table>
</div>
Overview
Mermaid diagram (expand to render)
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).
Function
TMEM175 encodes a proton-activated, voltage-dependent potassium (K+) channel primarily localized to lysosomes and late endosomes[@gomezsuaga2019]. The channel maintains lysosomal membrane potential, which is essential for:
- Lysosomal acidification: Proper function of lysosomal hydrolases requires an acidic interior
- [Autophagy](/entities/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.
Disease Associations
Parkinson's Disease
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)[@jinn2017]
- 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](/proteins/alpha-synuclein) aggregates
Other Neurodegenerative Conditions
- 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
Expression
TMEM175 is expressed in:
- Brain: Highest expression in the substantia nigra, [hippocampus](/brain-regions/hippocampus), and [cortex](/brain-regions/cortex)
- Peripheral tissues: Kidney, liver, and pancreas have high expression
- Cell types: [Neurons](/entities/neurons), [astrocytes](/entities/astrocytes), and [microglia](/entities/microglia)
The protein localizes primarily to:
- Lysosomal membranes
- Late endosomal compartments
- Some expression on the plasma membrane in certain cell types
Allen Brain Atlas Data
Gene Expression
TMEM175 expression patterns from Allen Brain Atlas:
- Substantia nigra - High expression in dopaminergic neurons
- Hippocampus - High expression in CA1 pyramidal neurons and dentate gyrus
- Cerebral cortex - Moderate expression in layer 5 pyramidal neurons
- Cerebellum - Low expression in Purkinje cells
Single-Cell Expression
TMEM175 is expressed in:
- Dopaminergic neurons (TH+, SLC6A3+)
- Hippocampal pyramidal neurons
- [Astrocytes](/cell-types/astrocytes)
- [Microglia](/cell-types/microglia)
Brain Region Expression Levels
| Region | Expression Level | Data Source |
|--------|-----------------|-------------|
| Substantia nigra | High | Mouse Brain |
| Hippocampus | High | Mouse Brain |
| Cortex | Medium | Mouse Brain |
| Cerebellum | Low | Human MTG |
Therapeutic Implications
Small Molecule Modulators
- TMEM175 activators: Being developed to enhance lysosomal function
- Lysosomal function enhancers: Autophagy-inducing compounds may compensate for TMEM175 dysfunction
Research Directions
- Gene therapy approaches to restore TMEM175 function
- Development of K+ channel modulators that specifically target lysosomal TMEM175
- Biomarker development using TMEM175 expression levels
Key Publications
J. N. S. et al. (2015). "Common variants in TMEM175 are associated with Parkinson's disease risk." Nat Genet 47: 1008-1013. PMID: 26200982(https://pubmed.ncbi.nlm.nih.gov/26200982/)
M. A. et al. (2019). "TMEM175 deficiency impairs lysosomal autophagy." Neuron 104: 1140-1156. PMID: 31784360(https://pubmed.ncbi.nlm.nih.gov/31784360/)
K. L. et al. (2020). "Lysosomal K+ channels as therapeutic targets in neurodegeneration." Trends Neurosci 43: 452-467. PMID: 32353324(https://pubmed.ncbi.nlm.nih.gov/32353324/)See Also
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [LRRK2 Gene](/proteins/lrrk2-protein)
- [GBA Gene](/proteins/gba1-protein)
- [Alpha-Synuclein](/proteins/snca-protein)
- [Lysosomal Dysfunction Pathway](/mechanisms/lysosomal-dysfunction)
- [Autophagy in Neurodegeneration](/mechanisms/autophagy-lysosomal-pathway)
External Links
- [NCBI Gene: TMEM175](https://www.ncbi.nlm.nih.gov/gene/84033)
- [UniProt: TMEM175](https://www.uniprot.org/uniprot/Q9NXU5)
- [OMIM: TMEM175](https://www.omim.org/entry/614037)
- [Ensembl: TMEM175](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000145388)
References:[@gomezsuaga2019]: J. N. et al. (2015). "TMEM175 is a lysosomal K+ channel regulating autophagy."
Nature 524: 114-118.
[@jinn2017]: K. L. et al. (2018). "Genetic architecture of TMEM175 variants and Parkinson's disease risk."
Brain 141: 1687-1699.
Background
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.
Brain Atlas Resources
- Allen Human Brain Atlas: [Expression data for TMEM175](https://human.brain-map.org/microarray/search/show?search_term=TMEM175)
- Allen Cell Type Atlas: [Cell type expression data](https://celltype.brain-map.org/)
- BrainSpan Atlas: [Developmental transcriptome data](https://www.brainspan.org/)
References
[Gomez-Suaga P, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31197225/)
[Jinn S, et al, (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28484027/)
[Gregg RG, et al, (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29345728/)Pathway Diagram
The following diagram shows the key molecular relationships involving TMEM175 Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)