title: Disease Mechanisms in ALS: Misfolded SOD1 Transferred Through Exosome-Dependent and Exosome-Independent Pathways.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neuromuscular degenerative disorder with a poorly defined etiology. ALS patients experience motor weakness, which starts focally and spreads throughout the nervous system, culminating in paralysis and death within a few years of diagnosis. While the vast majority of clinical ALS is sporadic with no known cause, mutations in human copper-zinc superoxide dismutase 1 (SOD1) cause about 20 % of inherited cases of ALS. ALS with SOD1 mutations is caused by a toxic gain of function associated with the propensity of mutant SOD1 to misfold, presenting a non-native structure. The mechanisms responsible for the progressive spreading of ALS pathology have been the focus of intense study. We have shown that misfolded SOD1 protein can seed misfolding and aggregation of endogenous wild-type SOD1 similar to amyloid-β and prion protein seeding. Our recent observations demonstrate a transfer of the misfolded SOD1 species from cell to cell, modeling the intercellular transmission of disease through the neuroaxis. We have shown that both mutant and misfolded wild-type SOD1 can traverse cell-to-cell, either as protein aggregates that are released from dying cells and taken up by neighboring cells via macropinocytosis, or in association with vesicles which are released into the extracellular environment. Furthermore, once misfolding of wild-type SOD1 has been initiated in a human cell culture, it can induce misfolding in naïve cell cultures over multiple passages of media transfer long after the initial misfolding template is degraded. Herein we review the data on mechanisms of intercellular transmission of misfolded SOD1.
authors.affiliation: Department of Medicine, Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Silverman
authors.affiliation: Department of Medicine, Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Fernando
authors.affiliation: Department of Medicine, Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Leslie I
authors.initials: LI
authors.lastname: Grad
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Yerbury
authors.affiliation: Department of Medicine, Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada. neil.cashman@vch.ca.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Cashman
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D066263:Protein Aggregation, Pathological / Q000201:enzymology; D017510:Protein Folding; D015398:Signal Transduction; D000072105:Superoxide Dismutase-1 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000072105:Superoxide Dismutase-1
keywords: ALS; Extracellular vesicle; Misfolded protein; Protein aggregate; SOD1