m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with mitochondria - PubMed
3 hours ago
- #Parkinson's disease
- #Mitochondrial dysfunction
- #RNA methylation
- m6A hypomethylation observed in the substantia nigra of mouse PD models and dysregulated METTL3 and ALKBH5 expression in dopaminergic neurons from PD patients.
- Preferential m6A deposition on transcripts of PD risk genes and a heterozygous METTL3 p.K480R mutation found in PD patients.
- Mettl3K480R/+ mice show progressive METTL3 reduction and m6A hypomethylation, leading to DA neuron loss, phospho-α-synuclein increase, and levodopa-responsive motor and non-motor deficits.
- Dopamine transporter-specific METTL3 knockout mice exhibit m6A hypomethylation, neurodegeneration, and levodopa-responsive parkinsonism.
- m6A deficiency disrupts mitochondrial biogenesis and function by regulating Tfam expression, while mitochondrial dysfunction impairs m6A deposition, creating a pathogenic loop.
- Supplementation with S-adenosylmethionine (SAMe) enhances m6A modification, disrupts the pathogenic loop, and alleviates parkinsonism in mouse models.
- Findings highlight m6A dysregulation as a key contributor to PD pathogenesis and suggest RNA methylation-targeted therapies as a promising intervention strategy.