FTO Protein (Fat Mass and Obesity-Associated Protein)

FTO Protein

<div class="infobox infobox-protein">
<div class="infobox-header">FTO Protein (Fat Mass and Obesity-Associated Protein)</div>

Overview

FTO Protein is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@hess2010]

<div class="infobox-row"><strong>Gene:</strong> [FTO](/genes/fto)</div> [@li2020]
<div class="infobox-row"><strong>UniProt:</strong> [Q9C0B1](https://www.uniprot.org/uniprot/Q9C0B1)</div> [@yao2023]
<div class="infobox-row"><strong>PDB:</strong> 5ZMD, 5IQN, 6I3J</div>
<div class="infobox-row"><strong>Molecular Weight:</strong> 58.6 kDa</div>
<div class="infobox-row"><strong>Subcellular Localization:</strong> Nucleus, cytoplasm</div>
<div class="infobox-row"><strong>Protein Family:</strong> AlkB family, Fe(II)/2-oxoglutarate-dependent dioxygenase family</div>
</div>

Structure

FTO Protein

<div class="infobox infobox-protein">
<div class="infobox-header">FTO Protein (Fat Mass and Obesity-Associated Protein)</div>

Overview

FTO Protein is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@hess2010]

<div class="infobox-row"><strong>Gene:</strong> [FTO](/genes/fto)</div> [@li2020]
<div class="infobox-row"><strong>UniProt:</strong> [Q9C0B1](https://www.uniprot.org/uniprot/Q9C0B1)</div> [@yao2023]
<div class="infobox-row"><strong>PDB:</strong> 5ZMD, 5IQN, 6I3J</div>
<div class="infobox-row"><strong>Molecular Weight:</strong> 58.6 kDa</div>
<div class="infobox-row"><strong>Subcellular Localization:</strong> Nucleus, cytoplasm</div>
<div class="infobox-row"><strong>Protein Family:</strong> AlkB family, Fe(II)/2-oxoglutarate-dependent dioxygenase family</div>
</div>

Structure

FTO (Fat Mass and Obesity-Associated Protein), also known as ALKBH9, is a 505-amino acid nuclear and cytoplasmic protein that functions as an N6-methyladenosine (m6A) demethylase. The protein belongs to the AlkB family of Fe(II)/2-oxoglutarate-dependent dioxygenases, which are evolutionarily conserved enzymes that catalyze the oxidative demethylation of nucleic acids and proteins. FTO contains an N-terminal AlkB-like domain (residues 1-326) that harbors the catalytic activity, and a C-terminal domain (residues 327-505) that is involved in substrate recognition and nuclear localization. The catalytic domain adopts a double-stranded beta-helix (DSBH) fold common to all Fe(II)/2-oxoglutarate-dependent dioxygenases, with conserved HxD...H motifs that coordinate the iron cofactor. FTO can demethylate m6A in single-stranded RNA and DNA, as well as other modified nucleobases including 3-methylthymine (m3T) and 3-methyluracil (m3U). The C-terminal domain contains a nuclear localization signal (NLS) and contributes to substrate specificity, with distinct regions recognizing RNA versus DNA substrates.

Normal Function in the Nervous System

FTO plays important roles in RNA metabolism and energy homeostasis in the nervous system:

• m6A Demethylation: FTO is the first discovered m6A demethylase, removing m6A modifications from mRNA and regulating RNA stability, translation, and splicing
• Energy Balance: FTO in the hypothalamus regulates food intake and energy expenditure; FTO variants are associated with obesity risk
• Neuronal Development: m6A demethylation regulates the timing of neuronal differentiation during development
• Synaptic Plasticity: FTO activity affects synaptic protein synthesis and plasticity; FTO knockdown impairs memory formation
• Stress Response: FTO expression is regulated by cellular stress, and its demethylase activity modulates stress response gene expression

Role in Neurodegeneration

Alzheimer's Disease

FTO expression and activity are altered in Alzheimer's disease brains. Studies show increased FTO expression in AD brain tissue, leading to reduced m6A levels on specific transcripts. This affects [amyloid precursor protein](/entities/app-protein) processing, [tau](/proteins/tau) phosphorylation, and synaptic plasticity genes. FTO demethylates APP mRNA, affecting its translation, and also regulates the expression of BACE1, the [beta-secretase](/entities/bace1) that generates [amyloid-beta](/proteins/amyloid-beta). The increased FTO activity in AD may contribute to the dysregulated RNA metabolism observed in the disease.

Parkinson's Disease

In Parkinson's disease, FTO plays complex roles in dopaminergic neuron survival. [Alpha-synuclein](/proteins/alpha-synuclein) mRNA is a substrate for FTO, and demethylation affects its translation efficiency. FTO also regulates the expression of mitochondrial function genes and [autophagy](/entities/autophagy)-related transcripts. Studies show that FTO inhibition can protect against dopaminergic neuron loss in PD models, suggesting that targeted inhibition may have therapeutic potential.

Stroke and Ischemia

FTO expression is regulated by cerebral ischemia, with increased FTO activity observed after stroke. The m6A demethylation of stress response transcripts affects neuronal survival after ischemic injury. FTO has been shown to be protective in some ischemia models through demethylation of pro-survival transcripts, while in other contexts it may promote damage through demethylation of inflammatory transcripts.

Intellectual Disability and Neurodevelopment

FTO variants are associated with intellectual disability and neurodevelopmental disorders. Loss-of-function mutations cause a syndrome characterized by severe intellectual disability, facial dysmorphism, and growth retardation. The role of FTO in brain development is mediated through m6A demethylation of transcripts encoding transcription factors and synaptic proteins essential for neuronal development.

Therapeutic Targeting

FTO is a promising therapeutic target for neurodegenerative diseases:

• Small Molecule Inhibitors: Rhein, FB23-2, and other FTO inhibitors are being developed for cancer and potentially for neurodegeneration
• m6A Modulation: Restoring m6A homeostasis through FTO modulation could normalize RNA metabolism in disease states
• Gene Therapy: AAV-mediated FTO knockdown or overexpression depending on the disease context
• Substrate-Specific Modulators: Drugs targeting specific FTO-RNA interactions may offer selectivity

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