Universität zu Köln

Altman, Topaz ORCID: 0000-0003-3075-894X, Ionescu, Ariel, Ibraheem, Amjad, Priesmann, Dominik, Gradus-Pery, Tal, Farberov, Luba, Alexandra, Gayster, Shelestovich, Natalia, Dafinca, Ruxandra ORCID: 0000-0003-0776-6431, Shomron, Noam, Rage, Florence, Talbot, Kevin, Ward, Michael E., Dori, Amir ORCID: 0000-0003-4633-1481, Kruger, Marcus and Perlson, Eran (2021). Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins. Nat. Commun., 12 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of similar to 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 hyperphosphorylated 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Altman, Topaz UNSPECIFIED orcid.org/0000-0003-3075-894X UNSPECIFIED Ionescu, Ariel UNSPECIFIED UNSPECIFIED UNSPECIFIED Ibraheem, Amjad UNSPECIFIED UNSPECIFIED UNSPECIFIED Priesmann, Dominik UNSPECIFIED UNSPECIFIED UNSPECIFIED Gradus-Pery, Tal UNSPECIFIED UNSPECIFIED UNSPECIFIED Farberov, Luba UNSPECIFIED UNSPECIFIED UNSPECIFIED Alexandra, Gayster UNSPECIFIED UNSPECIFIED UNSPECIFIED Shelestovich, Natalia UNSPECIFIED UNSPECIFIED UNSPECIFIED Dafinca, Ruxandra UNSPECIFIED orcid.org/0000-0003-0776-6431 UNSPECIFIED Shomron, Noam UNSPECIFIED UNSPECIFIED UNSPECIFIED Rage, Florence UNSPECIFIED UNSPECIFIED UNSPECIFIED Talbot, Kevin UNSPECIFIED UNSPECIFIED UNSPECIFIED Ward, Michael E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dori, Amir UNSPECIFIED orcid.org/0000-0003-4633-1481 UNSPECIFIED Kruger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Perlson, Eran UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-597069
DOI:	10.1038/s41467-021-27221-8
Journal or Publication Title:	Nat. Commun.
Volume:	12
Number:	1
Date:	2021
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RNA GRANULES; MOUSE MODEL; TRANSPORT; ALS; TRANSLATION; RECOVERY; TRANSCRIPTOME; DEGENERATION; MUTATIONS; REVEALS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59706