Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration
Georgia Dermentzaki,
Mattia Furlan,
Iris Tanaka,
Tommaso Leonardi,
Paola Rinchetti,
Patricia M.S. Passos,
Alliny Bastos,
Yuna M. Ayala,
Jacob H. Hanna,
Serge Przedborski,
Dario Bonanomi,
Mattia Pelizzola,
Francesco Lotti
Affiliations
Georgia Dermentzaki
Center for Motor Neuron Biology and Disease, Departments of Pathology & Cell Biology and Neurology, Columbia University, New York, NY, USA
Mattia Furlan
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy
Iris Tanaka
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy
Tommaso Leonardi
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy
Paola Rinchetti
Center for Motor Neuron Biology and Disease, Departments of Pathology & Cell Biology and Neurology, Columbia University, New York, NY, USA
Patricia M.S. Passos
Department of Biochemistry & Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri, USA
Alliny Bastos
Department of Biochemistry & Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri, USA
Yuna M. Ayala
Department of Biochemistry & Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri, USA
Jacob H. Hanna
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
Serge Przedborski
Center for Motor Neuron Biology and Disease, Departments of Pathology & Cell Biology and Neurology, Columbia University, New York, NY, USA; Department of Neuroscience, Columbia University, New York, NY, USA
Dario Bonanomi
Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Mattia Pelizzola
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
Francesco Lotti
Center for Motor Neuron Biology and Disease, Departments of Pathology & Cell Biology and Neurology, Columbia University, New York, NY, USA; Corresponding author
Summary: 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.
