<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Trehalase</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>TREH</td></tr>
<tr><td><strong>Full Name</strong></td><td>Trehalase</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>11q23.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[55281](https://www.ncbi.nlm.nih.gov/gene/55281)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[612161](https://www.omim.org/entry/612161)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000143537</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9NUH0](https://www.uniprot.org/uniprot/Q9NUH0)</td></tr>
<tr><td><strong>Protein Class</strong></td><td>Glycoside hydrolase family 37</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Alzheimer's Disease, Type 2 Diabetes, Metabolic Syndrome</td></tr>
</table>
</div>
<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Trehalase</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>TREH</td></tr>
<tr><td><strong>Full Name</strong></td><td>Trehalase</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>11q23.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[55281](https://www.ncbi.nlm.nih.gov/gene/55281)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[612161](https://www.omim.org/entry/612161)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000143537</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9NUH0](https://www.uniprot.org/uniprot/Q9NUH0)</td></tr>
<tr><td><strong>Protein Class</strong></td><td>Glycoside hydrolase family 37</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Alzheimer's Disease, Type 2 Diabetes, Metabolic Syndrome</td></tr>
</table>
</div>
TREH encodes trehalase, a hydrolytic enzyme that catalyzes the conversion of trehalose (α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside) into two glucose molecules. Trehalose is a non-reducing disaccharide found in many organisms, where it serves as a protectant against various environmental stresses. In mammals, trehalase is primarily expressed in the small intestine, kidney, liver, and brain. The enzyme exists in both membrane-bound and soluble forms, with distinct cellular localizations and functions. TREH has garnered significant interest due to its association with Alzheimer's disease risk through genome-wide association studies (GWAS) and the growing recognition of trehalose as a potential therapeutic agent in neurodegenerative diseases[@treh-structure][@treh-gwas][@lambert2009].
The TREH gene is located on chromosome 11q23.3 and encodes a protein of 583 amino acids. The gene structure includes multiple exons that undergo alternative splicing to produce different isoforms with distinct tissue distributions and cellular localizations[@treh-glycoside].
Trehalase belongs to glycoside hydrolase family 37 (GH37), characterized by:
| Feature | Description |
|---------|-------------|
| Molecular weight | ~65 kDa (membrane form) |
| Catalytic domain | GH37 signature motifs |
| Transmembrane region | For membrane-bound form |
| N-linked glycans | Multiple glycosylation sites |
The enzyme has a characteristic α/β-fold with active site residues that hydrolyze the α-1,1-glycosidic bond of trehalose. The membrane-bound form contains an N-terminal transmembrane helix that anchors the protein to the plasma membrane, while the soluble form is secreted or localized to the cytosol.
Multiple TREH isoforms have been identified:
TREH is significantly associated with Alzheimer's disease risk[@treh-gwas][@treh-neuroprotection]:
Genetic Association:
Trehalose shows promise in PD models[@treh-parkinson]:
Trehalose has shown remarkable effects in HD models[@treh-huntington][@pinto2016]:
Trehalose is a well-established mTOR-independent autophagy inducer[@sarkar2007][@treh-autophagy]:
Mechanism:
Key features:
This autophagy-enhancing property underlies much of trehalose's therapeutic potential[@kruger2020].
Trehalose metabolism involves several key steps:
Biosynthesis: In mammals, trehalose is obtained primarily from dietary sources. The intestinal enzyme trehalase (TREH) hydrolyzes trehalose to glucose, which enters the bloodstream and can be used for energy or stored as glycogen. Unlike many organisms, humans cannot synthesize trehalose endogenously, making dietary intake and TREH activity critical determinants of tissue trehalose levels.
Cellular uptake: Once absorbed, trehalose is distributed to various tissues including the brain. The mechanisms of brain uptake are incompletely understood but appear to involve both facilitated diffusion and transporter-mediated processes. Studies suggest that GLUT1 and GLUT3 may contribute to trehalose transport across the blood-brain barrier.
Intracellular effects: Inside cells, trehalose acts as a molecular chaperone, stabilizing proteins against denaturation and aggregation. This chaperone activity is separate from its autophagy-inducing effects and may contribute to neuroprotection through multiple mechanisms.
The mechanisms by which trehalose induces autophagy remain under investigation[@chen2023]:
mTOR-independent pathways: Unlike rapamycin, trehalose does not inhibit mTORC1. Instead, it appears to act through:
Synergy with other pathways: Trehalose works additively or synergistically with other autophagy inducers, making it attractive for combination therapy approaches.
Beyond autophagy, trehalose protects proteins through:
Protein stabilization: Trehalose preferentially excludes water from protein surfaces, promoting native folding and preventing denaturation. This "preferential hydration" mechanism maintains protein structure under stress conditions.
Aggregate prevention: By stabilizing folding intermediates, trehalose prevents the formation of toxic oligomers and aggregates that characterize many neurodegenerative diseases.
Stress resistance: Cells pretreated with trehalose show enhanced survival under various stresses including heat, oxidative stress, and nutrient deprivation.
Trehalose is being developed for multiple neurological indications:
A phase II trial in AD patients showed that oral trehalose was well-tolerated but had limited brain penetration at the doses tested. This has motivated efforts to develop improved formulations and delivery strategies.
Getting trehalose to the brain is challenging[@yang2024][@park2025]:
Nanoparticle encapsulation: Packaging trehalose in lipid nanoparticles or liposomes can enhance BBB penetration. These formulations protect trehalose from degradation and may leverage receptor-mediated transport.
Intranasal delivery: Direct nose-to-brain delivery bypasses the BBB partially and has shown promise in preclinical models.
Pro-drug approaches: Chemical modifications that improve lipophilicity can be cleaved by brain-resident enzymes to release active trehalose.
Focused ultrasound: Combining trehalose with focused ultrasound-mediated BBB opening enhances brain delivery in animal models.
Effective neuroprotective doses in animal studies typically range from:
While TREH is most highly expressed in intestine and kidney, it is also present in the brain:
Cellular distribution: TREH expression has been detected in:
TREH variants are associated with type 2 diabetes[@treh-diabetes]:
Genetic findings: GWAS have identified TREH variants that influence:
Trehalose metabolism in astrocytes has unique features[@johnson2025]:
Glycogen metabolism: Astrocytes store glycogen and release glucose for neuronal use. TREH may participate in glycogen mobilization pathways.
Neuroprotection: Astrocytic trehalose metabolism supports neuronal survival under stress conditions.
Metabolic coupling: TREH in astrocytes contributes to astrocyte-neuron metabolic coupling.
Current research priorities include:
The TREH-trehalose axis represents a promising target for neurodegenerative disease intervention, with the advantage of an established safety profile and multiple mechanisms of action.
Trehalase adopts a unique fold characteristic of glycoside hydrolase family 37:
Overall architecture: The enzyme consists of a single polypeptide chain with distinct domains:
The hydrolysis of trehalose proceeds through a double displacement mechanism:
Step 1 - Nucleophile attack: Glu451 acts as a nucleophile, attacking the anomeric carbon of the glucose moiety. This forms a covalent enzyme-substrate intermediate.
Step 2 - Acid/base catalysis: Simultaneously, Glu322 acts as a general acid, protonating the leaving group (the other glucose molecule).
Step 3 - Water attack: A water molecule attacks the covalent intermediate, assisted by Glu322 now acting as a general base.
Step 4 - Product release: Two glucose molecules are released, and the enzyme returns to its original state.
This mechanism ensures high catalytic efficiency and specificity for trehalose over other disaccharides.
The membrane-bound form of TREH contains additional structural features:
Transmembrane helix: An N-terminal hydrophobic helix (residues 1-20) anchors the protein in the plasma membrane.
Extracellular domain: The catalytic domain extends into the extracellular space (or lumen), where it encounters trehalose from the diet or environment.
Glycosylation: Multiple N-linked glycosylation sites on the extracellular domain affect stability and trafficking.
TREH is evolutionarily conserved across species:
Mammals: All mammals possess functional TREH genes with high sequence similarity. Human TREH shares ~85% identity with mouse TREH.
Lower organisms: Bacteria, fungi, and plants have trehalase enzymes, though these often belong to different families (GH15, GH65).
Enzymatic convergence: The catalytic mechanism of trehalases has evolved independently in different families, demonstrating the importance of trehalose metabolism across taxa.
Different species use trehalose for different purposes:
Stress protection: Many organisms accumulate trehalose as a stress protectant. This is particularly important for:
Signaling: Emerging evidence suggests trehalose may have signaling functions beyond its role as a nutrient.
TREH variants influence metabolic disease risk:
Type 2 Diabetes: GWAS have identified TREH variants associated with:
Trehalose metabolism may affect cancer biology:
Tumor metabolism: Some cancer cells show altered trehalose metabolism, potentially using it for energy or stress resistance.
Therapeutic potential: Trehalose may enhance the efficacy of chemotherapy by inducing autophagy in cancer cells.
Research status: This area is actively being explored, with implications for both cancer and neurodegenerative disease.
TREH may influence susceptibility to infections:
Pathogen interactions: Some pathogens utilize host trehalose, and TREH activity may affect infection outcomes.
Microbiome connections: Gut microbiome metabolism of dietary components influences TREH function and systemic effects.
TREH encodes trehalase, an enzyme at the intersection of carbohydrate metabolism, autophagy regulation, and neurodegenerative disease. The identification of TREH variants as AD risk factors through GWAS, combined with the therapeutic potential of trehalose in neurodegeneration, has generated significant interest in this gene. Key points include:
Continued research into TREH function and trehalose therapy holds promise for developing new treatments for AD, PD, HD, and ALS.
Trehalose is being developed for multiple neurological indications:
Getting trehalose to the brain is challenging:
The following diagram shows the key molecular relationships involving TREH — Trehalase discovered through SciDEX knowledge graph analysis: