FTO Protein is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [1]
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.
FTO plays important roles in RNA metabolism and energy homeostasis in the nervous system:
FTO is widely expressed in the brain, with high expression in the hypothalamus (regulating food intake), hippocampus (affecting learning and memory), and cortex. The protein localizes to both nucleus and cytoplasm, consistent with its roles in both nuclear RNA processing and cytoplasmic translation regulation.
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 processing, tau phosphorylation, and synaptic plasticity genes. FTO demethylates APP mRNA, affecting its translation, and also regulates the expression of BACE1, the beta-secretase that generates amyloid-beta. The increased FTO activity in AD may contribute to the dysregulated RNA metabolism observed in the disease.
In Parkinson's disease, FTO plays complex roles in dopaminergic neuron survival. 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-related transcripts. Studies show that FTO inhibition can protect against dopaminergic neuron loss in PD models, suggesting that targeted inhibition may have therapeutic potential.
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.
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.
FTO is a promising therapeutic target for neurodegenerative diseases:
Hess ME, et al. The fat mass and obesity associated gene (Fto) regulates food intake and body weight. Nature. 2010. ↩︎