Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration. Dermentzaki et al.

Description

Motor neurons (MNs) are the critical mediators of motor commands generated within the central nervous system (CNS) to peripheral muscle targets. Due to their unique function, MN demise is a hallmark of several neurodegenerative diseases, such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Post-transcriptional gene regulation can control RNA’s fate and function, and defects in RNA processing have been linked with MN loss. N6-methyladenosine (m6A), a post-transcriptional RNA modification with a prominent role in the CNS, controls diverse aspects of RNA metabolism, such as pre-mRNA splicing, nuclear export, stability, and translation. To assess the requirement of m6A in MNs, we depleted Mettl3 —the core m6A methyltransferase— in cells and mice. Mettl3 depletion in embryonic stem cell-derived MNs (ES-MNs) had profound and selective effects on MN survival and neurite outgrowth. Mice with MN-specific depletion of Mettl3 displayed a progressive decline in motor behaviors accompanied by MN loss and muscle denervation, culminating in paralysis and death starting at around eight months of age. Remarkably, only MNs innervating fast-fatigable muscles degenerated, while those innervating slow muscles were spared. The selectivity of this phenotype is reminiscent of the pattern of differential vulnerability observed in ALS. The effects of m6A modification are conveyed by “reader” proteins recruited to m6A-edited RNA sites. We found that depletion of Ythdf1 or Ythdf3 readers in ES-MNs phenocopied Mettl3 deletion, indicating that the action of m6A in MNs is reader-dependent and arguably mediated by subsets of modified transcripts. Among these m6A targets, we found Transactive response DNA-binding protein-43 (TDP-43) and discovered that its expression is under epitranscriptomic control. Thus, impaired m6A signaling disrupts MN homeostasis and triggers neurodegeneration conceivably through TDP-43 deregulation.

Institutions

Categories

Funding

Licence