TREH — Trehalase

TREH Gene — Trehalase

Pathway / Interaction Diagram

Overview

<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 Gene — Trehalase

Pathway / Interaction Diagram

Overview

<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].

Gene Structure and Protein Biochemistry

Genomic Organization

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].

Protein Structure

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.

Isoforms

Multiple TREH isoforms have been identified:

• Membrane-bound trehalase: Attached to cell membranes via transmembrane domain
• Soluble trehalase: Secreted or cytosolic localization
• Alternative splice variants: Tissue-specific expression

Role in Neurodegeneration

Alzheimer's Disease

TREH is significantly associated with Alzheimer's disease risk[@treh-gwas][@treh-neuroprotection]:

Genetic Association:

• GWAS identified TREH variants as risk loci for late-onset AD
• The association suggests a role for carbohydrate metabolism in AD
• TREH expression is altered in AD brain

• Trehalose enhances autophagy and clears Aβ plaques
• Reduces tau pathology in models
• Improves cognitive function in animal models
• May protect against synaptic loss

Parkinson's Disease

Trehalose shows promise in PD models[@treh-parkinson]:

• Alpha-synuclein clearance: Autophagy removes toxic species
• Dopaminergic neuron protection: Preserves vulnerable neurons
• Mitochondrial function: Improves energy metabolism
• Motor function: Improves behavioral outcomes

Huntington's Disease

Trehalose has shown remarkable effects in HD models[@treh-huntington][@pinto2016]:

• Clearance of mutant huntingtin protein
• Improved motor function
• Extended survival
• Reduced brain atrophy

Trehalose as a Therapeutic Agent

Trehalose is a well-established mTOR-independent autophagy inducer[@sarkar2007][@treh-autophagy]:

Mechanism:

Key features:

• Works through multiple pathways
• Does not affect cell growth at therapeutic doses
• Synergizes with other autophagy inducers

This autophagy-enhancing property underlies much of trehalose's therapeutic potential[@kruger2020].

Trehalose Metabolism and Cellular Effects

Metabolic Pathways

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.

Autophagy Induction 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:

• Activation of AMPK (AMP-activated protein kinase)
• Inhibition of glucose transporters
• Induction of cellular stress responses
• Modulation of transcription factors (TFEB)

Synergy with other pathways: Trehalose works additively or synergistically with other autophagy inducers, making it attractive for combination therapy approaches.

Molecular Chaperone Activity

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.

Clinical Development and Challenges

Clinical Trials

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.

Delivery Challenges

Getting trehalose to the brain is challenging[@yang2024][@park2025]:

• Blood-brain barrier penetration is limited by its hydrophilic nature
• High doses required for efficacy (often >10% of diet)
• Active transport systems being explored
• Alternative delivery routes under investigation

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.

Dosing Considerations

Effective neuroprotective doses in animal studies typically range from:

• Dietary: 2-10% of chow (w/w)
• Intraperitoneal: 2-4 g/kg
• Intravenous: 1-2 g/kg

TREH in Brain Biology

Expression in the Brain

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:

• Neurons (particularly in cortex and hippocampus)
• [Astrocytes](/cell-types/astrocytes) Microglia
• Vascular endothelial cells

TREH and Metabolic Disease

TREH variants are associated with type 2 diabetes[@treh-diabetes]:

Genetic findings: GWAS have identified TREH variants that influence:

• Fasting glucose levels
• Insulin sensitivity
• Type 2 diabetes risk

Astrocyte Functions

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.

Research Directions

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.

Protein Structure and Catalytic Mechanism

Three-Dimensional Structure

Trehalase adopts a unique fold characteristic of glycoside hydrolase family 37:

Overall architecture: The enzyme consists of a single polypeptide chain with distinct domains:

• An N-terminal catalytic domain (~450 residues)
• A C-terminal β-sandwich domain (~130 residues)
• A flexible linker region connecting these domains

• Two glutamic acid residues (Glu322 and Glu451) serve as catalytic acid/base
• A network of aromatic residues (Trp, Tyr, Phe) forms the substrate-binding pocket
• The active site accommodates the disaccharide in a flipped conformation

• How trehalose binds in the active site
• The catalytic mechanism involving proton transfer
• Why trehalase is highly specific for α-1,1-linked glucose dimers
• How mutations in TREH affect enzyme activity

Catalytic Mechanism

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.

Membrane Association

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.

Evolutionary Perspectives

Conservation

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.

Functional Divergence

Different species use trehalose for different purposes:

Stress protection: Many organisms accumulate trehalose as a stress protectant. This is particularly important for:

• Desiccation tolerance in tardigrades and nematodes
• Heat shock resistance in yeast
• Freezing tolerance in insects

Signaling: Emerging evidence suggests trehalose may have signaling functions beyond its role as a nutrient.

Disease Connections Beyond Neurodegeneration

Metabolic Disorders

TREH variants influence metabolic disease risk:

Type 2 Diabetes: GWAS have identified TREH variants associated with:

• Fasting glucose levels
• HbA1c
• Diabetes risk
• Response to glucose tolerance

• Intestinal glucose absorption
• Gut microbiome interactions
• Systemic inflammation

Cancer

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.

Infectious Diseases

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.

Summary

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.

Therapeutic Implications

Clinical Development

Trehalose is being developed for multiple neurological indications:

Delivery Challenges

Getting trehalose to the brain is challenging:

• Blood-brain barrier penetration is limited
• High doses required for efficacy
• Active transport systems being explored
• Alternative delivery routes under investigation

Cross-Links

• [Autophagy](/mechanisms/autophagy-lysosomal-pathway)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Glucose Metabolism](/mechanisms/glucose-metabolism)
• [Protein Aggregation](/mechanisms/protein-aggregation-neurodegeneration)
• [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction-pathway)
• [Amyloid Cascade Pathway](/mechanisms/amyloid-cascade-pathway)
• [mTOR Signaling](/mechanisms/mtor-signaling-neurodegeneration)

External Links

• [NCBI Gene - TREH](https://www.ncbi.nlm.nih.gov/gene/55281)
• [UniProt - Q9NUH0](https://www.uniprot.org/uniprot/Q9NUH0)
• [Ensembl - ENSG00000143537](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000143537)
• [OMIM - 612161](https://www.omim.org/entry/612161)
• [GeneCards: TREH](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TREH)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving TREH — Trehalase discovered through SciDEX knowledge graph analysis: