UMMS Affiliation
Department of Neurology
Publication Date
2017-03-08
Document Type
Article
Disciplines
Biochemistry, Biophysics, and Structural Biology | Nervous System Diseases | Neurology | Neuroscience and Neurobiology
Abstract
Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneration mainly affecting motor neurons. Evidence from transgenic mouse models suggests mutant forms of FUS exert an unknown gain-of-toxic function in motor neurons, but mechanisms underlying this effect remain unknown. Towards this end, we studied the effect of wild type FUS (FUS WT) and three ALS-linked variants (G230C, R521G and R495X) on fast axonal transport (FAT), a cellular process critical for appropriate maintenance of axonal connectivity. All ALS-FUS variants impaired anterograde and retrograde FAT in squid axoplasm, whereas FUS WT had no effect. Misfolding of mutant FUS is implicated in this process, as the molecular chaperone Hsp110 mitigated these toxic effects. Interestingly, mutant FUS-induced impairment of FAT in squid axoplasm and of axonal outgrowth in mammalian primary motor neurons involved aberrant activation of the p38 MAPK pathway, as also reported for ALS-linked forms of Cu, Zn superoxide dismutase (SOD1). Accordingly, increased levels of active p38 MAPK were detected in post-mortem human ALS-FUS brain tissues. These data provide evidence for a novel gain-of-toxic function for ALS-linked FUS involving p38 MAPK activation.
Keywords
Amyotrophic lateral sclerosis, Kinases, Mechanisms of disease, Motor proteins
Rights and Permissions
Copyright © The Author(s) 2017
DOI of Published Version
10.1038/s41598-017-00091-1
Source
Sci Rep. 2017 Mar 8;7(1):115. doi: 10.1038/s41598-017-00091-1. Link to article on publisher's site
Journal/Book/Conference Title
Scientific reports
Related Resources
PubMed ID
28273913
Repository Citation
Sama, Reddy Ranjith Kumar; Fallini, Claudia; Gatto, Rodolfo; McKeon, Jeanne E.; Song, Yuyu; Rotunno, Melissa S.; Penaranda, Saul; Abdurakhmanov, Izrail; Landers, John E.; Morfini, Gerardo; Brady, Scott T.; and Bosco, Daryl, "ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation" (2017). Open Access Articles. 3118.
https://escholarship.umassmed.edu/oapubs/3118
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Nervous System Diseases Commons, Neurology Commons, Neuroscience and Neurobiology Commons