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A CRMP4-dependent retrograde axon-to-soma death signal in amyotrophic lateral sclerosis
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SYSNO ASEP 0545405 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title A CRMP4-dependent retrograde axon-to-soma death signal in amyotrophic lateral sclerosis Author(s) Maimon, R. (IL)
Ankol, L. (IL)
Pery, T. G. (IL)
Altman, T. (IL)
Ionescu, A. (IL)
Weissová, Romana (FGU-C) ORCID, RID, SAI
Ostrovsky, M. (IL)
Tank, E. (US)
Alexandra, G. (IL)
Shelestovich, N. (IL)
Opatowsky, Y. (IL)
Dori, A. (IL)
Barmada, S. (US)
Balaštík, Martin (FGU-C) RID, ORCID
Perlson, E. (IL)Article number e107586 Source Title EMBO Journal. - : Wiley - ISSN 0261-4189
Roč. 40, č. 17 (2021)Number of pages 19 s. Language eng - English Country GB - United Kingdom Keywords ALS ; axonal transport ; CRMP4 ; dynein ; retrograde signaling Subject RIV FH - Neurology OECD category Clinical neurology R&D Projects NV18-04-00085 GA MZd - Ministry of Health (MZ) GA21-24571S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support FGU-C - RVO:67985823 UT WOS 000668140200001 EID SCOPUS 85108976518 DOI 10.15252/embj.2020107586 Annotation Amyotrophic lateral sclerosis (ALS) is a fatal non-cell-autonomous neurodegenerative disease characterized by the loss of motor neurons (MNs). Mutations in CRMP4 are associated with ALS in patients, and elevated levels of CRMP4 are suggested to affect MN health in the SOD1G93A-ALS mouse model. However, the mechanism by which CRMP4 mediates toxicity in ALS MNs is poorly understood. Here, by using tissue from human patients with sporadic ALS, MNs derived from C9orf72-mutant patients, and the SOD1G93A-ALS mouse model, we demonstrate that subcellular changes in CRMP4 levels promote MN loss in ALS. First, we show that while expression of CRMP4 protein is increased in cell bodies of ALS-affected MN, CRMP4 levels are decreased in the distal axons. Cellular mislocalization of CRMP4 is caused by increased interaction with the retrograde motor protein, dynein, which mediates CRMP4 transport from distal axons to the soma and thereby promotes MN loss. Blocking the CRMP4-dynein interaction reduces MN loss in human-derived MNs (C9orf72) and in ALS model mice. Thus, we demonstrate a novel CRMP4-dependent retrograde death signal that underlies MN loss in ALS. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2022 Electronic address https://doi.org/10.15252/embj.2020107586
Number of the records: 1