title: Extracellular wildtype and mutant SOD1 induces ER-Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ER-Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER-Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ER-Golgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS.
authors.affiliation: Department of Biochemistry, Latrobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC, 3086, Australia.
authors.forename: Vinod
authors.initials: V
authors.lastname: Sundaramoorthy
authors.forename: Adam K
authors.initials: AK
authors.lastname: Walker
authors.forename: Justin
authors.initials: J
authors.lastname: Yerbury
authors.forename: Kai Ying
authors.initials: KY
authors.lastname: Soo
authors.forename: Manal A
authors.initials: MA
authors.lastname: Farg
authors.forename: Vy
authors.initials: V
authors.lastname: Hoang
authors.forename: Rafaa
authors.initials: R
authors.lastname: Zeineddine
authors.forename: Damian
authors.initials: D
authors.lastname: Spencer
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D017510:Protein Folding; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1