ALKBH5 Protein (AlkB Homolog 5)

ALKBH5 Protein

<div class="infobox infobox-protein">
<div class="infobox-header">ALKBH5 Protein (AlkB Homolog 5)</div>

Overview

ALKBH5 Protein is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@zhang2022]

<div class="infobox-row"><strong>Gene:</strong> [ALKBH5](/genes/alkbh5)</div> [@yu2024]
<div class="infobox-row"><strong>UniProt:</strong> [Q6P6X2](https://www.uniprot.org/uniprot/Q6P6X2)</div> [@cho2023]
<div class="infobox-row"><strong>PDB:</strong> 4NRO, 4OA4, 5TJJ</div>
<div class="infobox-row"><strong>Molecular Weight:</strong> 29.4 kDa</div>
<div class="infobox-row"><strong>Subcellular Localization:</strong> Nucleus</div>
<div class="infobox-row"><strong>Protein Family:</strong> AlkB family, Fe(II)/2-oxoglutarate-dependent dioxygenase family</div>
</div>

Structure

ALKBH5 Protein

<div class="infobox infobox-protein">
<div class="infobox-header">ALKBH5 Protein (AlkB Homolog 5)</div>

Overview

ALKBH5 Protein is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@zhang2022]

<div class="infobox-row"><strong>Gene:</strong> [ALKBH5](/genes/alkbh5)</div> [@yu2024]
<div class="infobox-row"><strong>UniProt:</strong> [Q6P6X2](https://www.uniprot.org/uniprot/Q6P6X2)</div> [@cho2023]
<div class="infobox-row"><strong>PDB:</strong> 4NRO, 4OA4, 5TJJ</div>
<div class="infobox-row"><strong>Molecular Weight:</strong> 29.4 kDa</div>
<div class="infobox-row"><strong>Subcellular Localization:</strong> Nucleus</div>
<div class="infobox-row"><strong>Protein Family:</strong> AlkB family, Fe(II)/2-oxoglutarate-dependent dioxygenase family</div>
</div>

Structure

ALKBH5 (AlkB Homolog 5) is a 259-amino acid nuclear protein that functions as an N6-methyladenosine (m6A) demethylase. As a member of the AlkB family of Fe(II)/2-oxoglutarate-dependent dioxygenases, ALKBH5 catalyzes the oxidative demethylation of m6A in messenger RNA. The protein consists of a catalytic domain (residues 66-230) that adopts the characteristic double-stranded beta-helix (DSBH) fold, with conserved HxD...H and RxS motif coordinates the iron cofactor and 2-oxoglutarate binding. Unlike FTO, ALKBH5 shows high specificity for m6A in RNA and does not demethylate DNA substrates. The protein contains an N-terminal region that contributes to subcellular localization and protein-protein interactions, and a C-terminal region that participates in substrate recognition. ALKBH5 is primarily localized to the nucleus, where it demethylates m6A co-transcriptionally, influencing RNA processing events including splicing, export, and translation.

Normal Function in the Nervous System

ALKBH5 plays important roles in RNA metabolism and neuronal function:

• m6A Demethylation: ALKBH5 removes m6A modifications from mRNA, regulating RNA stability, splicing, and translation
• Synaptic Plasticity: ALKBH5 activity regulates synaptic protein synthesis and affects learning and memory formation
• Neuronal Development: m6A demethylation by ALKBH5 regulates the expression of neurodevelopmental genes
• Stress Response: ALKBH5 is recruited to stress granules under cellular stress, where it demethylates mRNAs involved in stress response
• [Long-Term Potentiation](/mechanisms/long-term-potentiation): ALKBH5 deficiency impairs LTP and memory formation through dysregulated m6A methylation

Role in Neurodegeneration

Alzheimer's Disease

ALKBH5 expression is altered in [Alzheimer's disease](/diseases/alzheimers-disease), contributing to dysregulated m6A homeostasis. Studies show increased ALKBH5 expression in AD brains, leading to reduced m6A levels on key transcripts including [APP](/entities/app-protein) and [tau](/proteins/tau) mRNAs. This affects [amyloid-beta](/proteins/amyloid-beta) production and tau pathology. The m6A reader YTHDF1, which promotes translation, shows altered expression in AD, compounding the dysregulation. ALKBH5-mediated demethylation affects the splicing of tau isoforms, contributing to the accumulation of toxic tau species.

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), ALKBH5 plays important roles in regulating mitochondrial function and [alpha-synuclein](/proteins/alpha-synuclein) metabolism. Alpha-synuclein mRNA is modified by m6A, and ALKBH5 demethylation affects its translation and aggregation propensity. ALKBH5 also regulates the expression of mitochondrial dynamics genes through m6A demethylation, affecting dopaminergic neuron survival. ALKBH5 is recruited to stress granules in PD models, where it regulates the translation of stress response genes.

Amyotrophic Lateral Sclerosis (ALS)

ALKBH5 dysfunction contributes to ALS pathogenesis through altered m6A regulation of transcripts encoding RNA-binding proteins. [TDP-43](/mechanisms/tdp-43-proteinopathy) and FUS mRNAs are substrates for ALKBH5, and demethylation affects their splicing and expression. The stress granule localization of ALKBH5 is relevant to ALS, where stress granule dynamics are disrupted. Modulating ALKBH5 activity may offer therapeutic benefits in ALS.

Stroke and Ischemia

Following cerebral ischemia, ALKBH5 is recruited to stress granules and regulates the translation of survival genes. Studies show that ALKBH5 knockdown exacerbates neuronal damage after ischemia, while ALKBH5 overexpression is protective. The m6A demethylation of pro-survival transcripts promotes their translation under stress conditions.

Therapeutic Targeting

ALKBH5 is a promising therapeutic target:

• Small Molecule Modulators: Selective ALKBH5 inhibitors are being developed for cancer and neurological applications
• m6A Homeostasis Restoration: Modulating ALKBH5 activity could restore normal m6A levels in disease states
• Stress Granule Modulators: Since ALKBH5 localizes to stress granules, targeting this pathway may help in ALS and other stress-related disorders
• Gene Therapy: AAV-mediated ALKBH5 modulation could be beneficial depending on disease context

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References