<div class="infobox infobox-protein">
<div class="infobox-header">ALKBH5 Protein (AlkB Homolog 5)</div>
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>
<div class="infobox infobox-protein">
<div class="infobox-header">ALKBH5 Protein (AlkB Homolog 5)</div>
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>
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.
ALKBH5 plays important roles in RNA metabolism and neuronal function:
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.
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.
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.
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.
ALKBH5 is a promising therapeutic target: