Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration

Abstract

Motor neuron (MN) demise is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Post-transcriptional gene regulation can control RNA's fate, and defects in RNA processing are critical determinants of MN degeneration. N⁶-methyladenosine (m⁶A) is a post-transcriptional RNA modification that controls diverse aspects of RNA metabolism. To assess the m⁶A requirement in MNs, we depleted the m⁶A methyltransferase-like 3 (METTL3) in cells and mice. METTL3 depletion in embryonic stem cell-derived MNs has profound and selective effects on survival and neurite outgrowth. Mice with cholinergic neuron-specific METTL3 depletion display a progressive decline in motor behavior, accompanied by MN loss and muscle denervation, culminating in paralysis and death. Reader proteins convey m⁶A effects, and their silencing phenocopies METTL3 depletion. Among the m⁶A targets, we identified 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.

Keywords: ALS; CP: Neuroscience; FTD; METTL3; N6-methyladenosine; RNA epigenetics; RNA metabolism; TDP-43; age-related neurodegeneration; amyotrophic lateral sclerosis; frontotemporal dementia; m6A; methyltransferase-like 3; motor neurons; transactive response DNA-binding protein-43.