TMEM55A — Transmembrane Protein 55A
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TMEM55A — Transmembrane Protein 55A</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TMEM55A</strong></td>
</tr>
<tr>
<td class="label">Current Symbol</td>
<td><strong>PIP4P2</strong> (Phosphatidylinositol-4,5-bisphosphate 4-phosphatase 2)</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Transmembrane protein 55A / Type 2 PtdIns-4,5-P2 4-phosphatase</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>8q13.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/55529" target="_blank">55529</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000149547" target="_blank">ENSG00000149547</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/609864" target="_blank">609864</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprotkb/Q8N4L2" target="_blank">Q8N4L2</a></td>
</tr>
<tr>
<td class="label">Protein</td>
<td>PIP4P2 (257 aa, Type II transmembrane lysosomal protein)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease) (therapeutic target)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Brain](/brain-regions/brain), [Substantia Nigra](/brain-regions/substantia-nigra), lysosomal compartments</td>
</tr>
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<th class="infobox-subheader" colspan="2">Key Aliases</th>
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<tr>
<td colspan="2" style="font-size:0.85em">PIP4P2, PP4P2, TMEM55A, MDP1, NTP3</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
TMEM55A — Transmembrane Protein 55A
Introduction
TMEM55A (current official symbol: PIP4P2, also known as phosphatidylinositol-4,5-bisphosphate 4-phosphatase 2) is a gene on chromosome 8q13.1 encoding a 257-amino acid Type II transmembrane protein localized primarily to lysosomal membranes. Originally cloned and characterized in 2006,[@pubmed16365287] TMEM55A has emerged as a novel therapeutic target in [Parkinson's disease](/diseases/parkinsons-disease) based on recent multi-omics network analysis demonstrating its role in endolysosomal pathway dysfunction[@pubmed41866087].
TMEM55A is a transmembrane protein localized to endolysosomal membranes where it plays a critical role in regulating phosphatidylinositol (PI) signaling and lysosomal function.
Gene Structure and Protein
Gene Organization
- Chromosome: 8q13.1 (NC_000008.11: 90993802..91040859)
- Genomic span: ~47 kb
- RefSeq transcript: NM_018710.3 (2,759 nt)
- Protein: NP_061180.1 (257 aa, MANE Select)
- OMIM: 609864
Protein Structure
TMEM55A/PIP4P2 is a Type II transmembrane protein with:
- A short N-terminal cytoplasmic domain
- A single transmembrane helix
- A large C-terminal luminal domain containing the phosphatase catalytic activity
- Localizes to lysosomal membranes
The protein catalyzes the hydrolysis of [phosphatidylinositol-4,5-bisphosphate](/proteins/pip2) (PtdIns-4,5-P2) to phosphatidylinositol-4-phosphate (PtdIns-4-P), making it a key regulator of phosphoinositide signaling at the lysosomal membrane.
Normal Function
TMEM55A functions as a type 2 phosphatidylinositol-4,5-bisphosphate 4-phosphatase (EC 3.1.3.78) with the following enzymatic properties:
- Substrate: Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2)
- Product: Phosphatidylinositol-4-phosphate (PtdIns-4-P)
The enzyme does not hydrolyze other phosphoinositides including:
- Phosphatidylinositol 3,4,5-trisphosphate (PIP3)
- Phosphatidylinositol 3,4-bisphosphate
- Inositol 3,5-bisphosphate
- Inositol 3,4-bisphosphate
- Phosphatidylinositol 5-monophosphate
- Phosphatidylinositol 4-monophosphate
- Phosphatidylinositol 3-monophosphate
This substrate specificity positions TMEM55A as a specific regulator of the PtdIns-4,5-P2 pool at lysosomal membranes.
Lysosomal Membrane Biology
TMEM55A is predominantly localized to lysosomal membranes where it regulates:
- Lysosomal membrane composition and integrity
- Phosphoinositide-dependent signaling at the lysosome
- Endolysosomal trafficking pathways
Role in Parkinson's Disease
Endolysosomal Pathway Dysfunction
TMEM55A is implicated in [Parkinson's disease](/diseases/parkinsons-disease) pathogenesis through its involvement in the endolysosomal pathway—a cellular system critical for protein degradation, membrane recycling, and autophagy. The endolysosomal pathway is one of several key cellular systems dysregulated in PD, alongside mitochondrial dysfunction, neuroinflammation, and protein aggregation.
Key findings from PMID:41866087:
- TMEM55A is located within phosphatidylinositol cycle subnetworks of the endolysosomal pathway
- Genetic manipulation of TMEM55A ameliorates behavioral deficits in Drosophila PD models
- TMEM55A targeting reduces neurodegeneration and protects dopaminergic neurons
- Represents a potential therapeutic node identified through integrative multi-omic network analysis
Phosphatidylinositol Signaling
TMEM55A participates in phosphatidylinositol (PI) metabolism, which regulates:
- Endosomal trafficking and sorting
- Lysosomal function and biogenesis
- Autophagosome formation and fusion
- Membrane lipid composition
Dysregulation of PI signaling contributes to [alpha-synuclein](/proteins/alpha-synuclein) accumulation, impaired autophagy, and dopaminergic neuron vulnerability—all hallmarks of PD pathogenesis.
Therapeutic Potential
TMEM55A represents a promising therapeutic target because:
Genetic validation: Knockdown/knockout studies show neuroprotection in vivo
Disease modification: Targets upstream endolysosomal dysfunction rather than just symptoms
Dopaminergic specificity: Particularly vulnerable neuron population benefits
Novel mechanism: Complements existing therapeutic approaches
Relationship to Other PD Genes
- [TMEM55B](/genes/tmem55b) — paralog with similar function
- [LRRK2](/genes/lrrk2) — another kinase linked to endolysosomal dysfunction in PD
- [GBA](/genes/gba) — glucocerebrosidase, major risk gene affecting lysosomal function
- [PARKIN](/genes/parkin) — mitophagy and endolysosomal trafficking
- [PINK1](/genes/pink1) — mitochondrial quality control linked to lysosomal function
- [Endolysosomal Pathway in Neurodegeneration](/mechanisms/endosomal-lysosomal-pathway)
- [Lysosomal Dysfunction in AD/PD](/mechanisms/lysosomal-dysfunction)
- [Autophagy-Lysosome Pathway](/mechanisms/autophagy-lysosome-pathway)
- [Phosphatidylinositol Signaling](/mechanisms/phosphoinositide-signaling)
Comparison with TMEM55B
TMEM55A (PIP4P2) is closely related to TMEM55B (PIP4P1) on chromosome 14q11.2:
| Feature | TMEM55A (PIP4P2) | TMEM55B (PIP4P1) |
|---------|------------------|------------------|
| Gene ID | 55529 | 90809 |
| Chromosome | 8q13.1 | 14q11.2 |
| Protein Length | 257 aa | 277 aa |
| UniProt | Q8N4L2 | Q86T03 |
| OMIM | 609864 | 609865 |
Both proteins function as phosphatidylinositol-4,5-bisphosphate 4-phosphatases and are implicated in lysosomal positioning and endolysosomal biology. The 2025 multi-omic study identified both as potential therapeutic targets in PD.
Brain Atlas Resources
- [Allen Human Brain Atlas: TMEM55A search](https://human.brain-map.org/microarray/search/show?search_term=TMEM55A)
- [Allen Mouse Brain Atlas: TMEM55A search](https://mouse.brain-map.org/search/index.html?query=TMEM55A)
- [BrainSpan Developmental Transcriptome](https://www.brainspan.org)
External Links
- [NCBI Gene: 55529 (TMEM55A/PIP4P2)](https://www.ncbi.nlm.nih.gov/gene/55529)
- [UniProt: Q8N4L2](https://www.uniprot.org/uniprotkb/Q8N4L2)
- [OMIM: 609864](https://omim.org/entry/609864)
- [Ensembl: ENSG00000149547](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000149547)
- [GeneCards: TMEM55A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM55A)
See Also
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
- [LRRK2](/genes/lrrk2)
- [GBA](/genes/gba)
- [Endolysosomal Pathway](/mechanisms/endolysosomal-pathway)
- [Phosphatidylinositol Signaling](/mechanisms/phosphoinositide-signaling)
- [Dopaminergic Neurons](/cell-types/dopaminergic-neurons)
- [TMEM55B](/genes/tmem55b)
References
[Kong et al., Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (2006)](https://pubmed.ncbi.nlm.nih.gov/16365287/)
[Lau et al., Integrative multi-omic network analysis identifies molecular targets for Parkinson's disease (2025)](https://pubmed.ncbi.nlm.nih.gov/41866087/)