Abstract
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.
| Original language | English |
|---|---|
| Article number | e107586 |
| Journal | EMBO Journal |
| Volume | 40 |
| Issue number | 17 |
| DOIs | |
| State | Published - 1 Sep 2021 |
Bibliographical note
Publisher Copyright:© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license
Funding
This work was supported by IsrALS Foundation, the Israel Science Foundation (735/19), Ministry of Science and Technology State of Israel, and the European Research Council (grant number 309377) to E.P, Czech Health Research Council grant no. NV18-04-00085 to MB, Czech Science Foundation grant no. 21-24571S to MB and RW, and Grant Agency of the Charles University grants no. 524218 to RW. We thank Prof. Mike Fainzilber for the Tamra peptides, and help with AAV9 design. We thank Prof. Eva Feldman and Prof. Stephen Goutman for obtaining the fibroblasts for the IPSC lines. We thank Dr. Michael Tolmasov for performing the intrathecal injections. We thanks Michigan Brain Bank (5P30 AG053760 University of Michigan Alzheimer’s Disease Core Center) for providing patients spinal cord sections. Immunohistochemistry (IHC) was performed at the Rogel Cancer Center Tissue and Molecular Pathology Shared Resource Laboratory (funding support: NIH P30 CA04659229). This work was supported by IsrALS Foundation, the Israel Science Foundation (735/19), Ministry of Science and Technology State of Israel, and the European Research Council (grant number 309377) to E.P, Czech Health Research Council grant no. NV18‐04‐00085 to MB, Czech Science Foundation grant no. 21‐24571S to MB and RW, and Grant Agency of the Charles University grants no. 524218 to RW. We thank Prof. Mike Fainzilber for the Tamra peptides, and help with AAV9 design. We thank Prof. Eva Feldman and Prof. Stephen Goutman for obtaining the fibroblasts for the IPSC lines. We thank Dr. Michael Tolmasov for performing the intrathecal injections. We thanks Michigan Brain Bank (5P30 AG053760 University of Michigan Alzheimer’s Disease Core Center) for providing patients spinal cord sections. Immunohistochemistry (IHC) was performed at the Rogel Cancer Center Tissue and Molecular Pathology Shared Resource Laboratory (funding support: NIH P30 CA04659229).
| Funders | Funder number |
|---|---|
| Grant Agency of the Charles University | 524218 |
| IsrALS Foundation | |
| Michigan Brain Bank | 5P30 AG053760 |
| Rogel Cancer Center Tissue and Molecular Pathology Shared Resource Laboratory | |
| National Institutes of Health | P30 CA04659229 |
| National Institute on Aging | P30AG053760 |
| European Commission | 309377 |
| Ministry of Science, Technology and Space | |
| Grantová Agentura České Republiky | 21‐24571S |
| Israel Science Foundation | 735/19 |
| Agentura Pro Zdravotnický Výzkum České Republiky | NV18‐04‐00085 |
Keywords
- ALS
- CRMP4
- axonal transport
- dynein
- retrograde signaling
