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Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins
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Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins
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Journal Article
Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins
2021
Overview
Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model. In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development.
Here, the authors show in human iPSC-derived motor neurons from ALS patients and a TDP-43 mouse model that axonal TDP-43 forms G3BP1 positive RNP condensates, which sequester mRNA of nuclear encoded mitochondrial proteins and decrease local protein synthesis in motor neuron axons and neuromuscular junctions.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/51
/ 13/62
/ 14
/ 14/19
/ 64
/ 64/110
/ 96
/ Amyotrophic Lateral Sclerosis
/ Amyotrophic Lateral Sclerosis - drug therapy
/ Animals
/ Axons
/ DNA-Binding Proteins - chemistry
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ DNA-Binding Proteins - pharmacology
/ Female
/ Humanities and Social Sciences
/ Humans
/ Induced Pluripotent Stem Cells
/ Mice
/ Mitochondrial Proteins - chemistry
/ Mitochondrial Proteins - genetics
/ Mitochondrial Proteins - metabolism
/ mRNA
/ Nerves
/ Neurodegenerative Diseases - drug therapy
/ Neuromuscular Junction - drug effects
/ Neuromuscular Junction - metabolism
/ Neurons
/ Poly-ADP-Ribose Binding Proteins
/ Proteins
/ RNA Recognition Motif Proteins
/ Science
/ Toxicity
