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A CRMP4-dependent retrograde axon-to-soma death signal in amyotrophic lateral sclerosis
- 1.0545405 - FGÚ 2022 RIV GB eng J - Journal Article
Maimon, R. - Ankol, L. - Pery, T. G. - Altman, T. - Ionescu, A. - Weissová, Romana - Ostrovsky, M. - Tank, E. - Alexandra, G. - Shelestovich, N. - Opatowsky, Y. - Dori, A. - Barmada, S. - Balaštík, Martin - Perlson, E.
A CRMP4-dependent retrograde axon-to-soma death signal in amyotrophic lateral sclerosis.
EMBO Journal. Roč. 40, č. 17 (2021), č. článku e107586. ISSN 0261-4189. E-ISSN 1460-2075
R&D Projects: GA MZd(CZ) NV18-04-00085; GA ČR(CZ) GA21-24571S
Institutional support: RVO:67985823
Keywords : ALS * axonal transport * CRMP4 * dynein * retrograde signaling
OECD category: Clinical neurology
Impact factor: 13.783, year: 2021
Method of publishing: Open access
https://doi.org/10.15252/embj.2020107586
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.
Permanent Link: http://hdl.handle.net/11104/0322102
Number of the records: 1