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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.

Original publication

DOI

10.1038/s41467-021-27221-8

Type

Journal article

Journal

Nature communications

Publication Date

11/2021

Volume

12

Addresses

Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Keywords

Neurons, Axons, Neurons, Efferent, Motor Neurons, Neuromuscular Junction, Mitochondria, Animals, Mice, Inbred C57BL, Humans, Mice, Amyotrophic Lateral Sclerosis, Neurodegenerative Diseases, Disease Models, Animal, DNA Helicases, RNA Helicases, DNA-Binding Proteins, Mitochondrial Proteins, Phosphorylation, Female, Induced Pluripotent Stem Cells, RNA Recognition Motif Proteins, C9orf72 Protein, Poly-ADP-Ribose Binding Proteins, Inhibition, Psychological