Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins

Topaz Altman, Ariel Ionescu, Amjad Ibraheem, Dominik Priesmann, Tal Gradus-Pery, Luba Farberov, Gayster Alexandra, Natalia Shelestovich, Ruxandra Dafinca, Noam Shomron, Florence Rage, Kevin Talbot, Michael E. Ward, Amir Dori, Marcus Krüger and Eran Perlson ()
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Topaz Altman: Sackler Faculty of Medicine, Tel-Aviv University
Ariel Ionescu: Sackler Faculty of Medicine, Tel-Aviv University
Amjad Ibraheem: Sackler Faculty of Medicine, Tel-Aviv University
Dominik Priesmann: CECAD Research Center and Center for Molecular Medicine (CMMC), University of Cologne
Tal Gradus-Pery: Sackler Faculty of Medicine, Tel-Aviv University
Luba Farberov: Sackler Faculty of Medicine, Tel-Aviv University
Gayster Alexandra: Pathology Institute, Sheba Medical Center, Tel Hashomer
Natalia Shelestovich: Pathology Institute, Sheba Medical Center, Tel Hashomer
Ruxandra Dafinca: University of Oxford
Noam Shomron: Sackler Faculty of Medicine, Tel-Aviv University
Florence Rage: Institut de Génétique Moléculaire de Montpellier
Kevin Talbot: University of Oxford
Michael E. Ward: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Amir Dori: Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University
Marcus Krüger: CECAD Research Center and Center for Molecular Medicine (CMMC), University of Cologne
Eran Perlson: Sackler Faculty of Medicine, Tel-Aviv University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27221-8

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