m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Parkinson's disease (PD) molecular pathology is not fully understood, with unknown drivers in many cases.
• Selective N6-methyladenosine (m6A) hypomethylation observed in mouse PD models and altered METTL3/ALKBH5 expression in PD patient neurons suggest a role for RNA modification.

Purpose of the Study:

• To investigate the role of RNA modification, particularly m6A, in Parkinson's disease.
• To explore the therapeutic potential of targeting RNA methylation for PD intervention.

Main Methods:

• Analysis of m6A deposition on PD risk gene transcripts.
• Characterization of a novel METTL3 mutation (p.K480R) in PD patients and its effects in Mettl3K480R/+ mice.
• Generation of dopamine transporter-specific METTL3 knockout mice.
• Investigation of the mechanistic link between m6A, mitochondrial function (Tfam expression), and PD pathogenesis.
• Assessment of S-adenosylmethionine (SAMe) supplementation in mouse models.

Main Results:

• Preferential m6A deposition on PD risk gene transcripts was identified.
• The METTL3 p.K480R mutation leads to progressive m6A hypomethylation, dopaminergic neuron loss, and PD-like motor/non-motor deficits in mice.
• METTL3 deficiency in dopaminergic neurons recapitulates PD hallmarks, including neurodegeneration and levodopa-responsive parkinsonism.
• m6A deficiency impairs mitochondrial biogenesis and function via Tfam regulation, creating a pathogenic feedback loop.
• SAMe supplementation reversed m6A dysregulation, disrupted the pathogenic loop, and alleviated parkinsonism in mouse models.

Conclusions:

• m6A RNA dysregulation is a significant contributor to Parkinson's disease pathogenesis.
• METTL3 dysfunction and subsequent m6A hypomethylation drive dopaminergic neurodegeneration and parkinsonism.
• Targeting RNA methylation, for example, via SAMe supplementation, represents a promising therapeutic strategy for Parkinson's disease.