TY - JOUR
T1 - Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration
AU - Dermentzaki, Georgia
AU - Furlan, Mattia
AU - Tanaka, Iris
AU - Leonardi, Tommaso
AU - Rinchetti, Paola
AU - Passos, Patricia M.S.
AU - Bastos, Alliny
AU - Ayala, Yuna M.
AU - Hanna, Jacob H.
AU - Przedborski, Serge
AU - Bonanomi, Dario
AU - Pelizzola, Mattia
AU - Lotti, Francesco
PY - 2024/4/23
Y1 - 2024/4/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85189559069&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2024.113999
DO - 10.1016/j.celrep.2024.113999
M3 - Article
C2 - 38554281
AN - SCOPUS:85189559069
SN - 2211-1247
VL - 43
JO - Cell Reports
JF - Cell Reports
IS - 4
M1 - 113999
ER -