title: SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation.
abstract: BACKGROUND
  Amyotrophic Lateral Sclerosis is characterized by a focal onset of symptoms followed by a progressive spread of pathology that has been likened to transmission of infectious prions. Cell-to-cell transmission of SOD1 protein aggregates is dependent on fluid-phase endocytosis pathways, although the precise molecular mechanisms remain to be elucidated.
  
  
  RESULTS
  We demonstrate in this paper that SOD1 aggregates interact with the cell surface triggering activation of Rac1 and subsequent membrane ruffling permitting aggregate uptake via stimulated macropinocytosis. In addition, other protein aggregates, including those associated with neurodegenerative diseases (TDP-43, Httex146Q, α-synuclein) also trigger membrane ruffling to gain entry into the cell. Aggregates are able to rupture unstructured macropinosomes to enter the cytosol allowing propagation of aggregation to proceed.
  
  
  CONCLUSIONS
  Thus, we conclude that in addition to basic proteostasis mechanisms, pathways involved in the activation of macropinocytosis are key determinants in the spread of pathology in these misfolding diseases.
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. rz770@uowmail.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. rz770@uowmail.edu.au.
authors.forename: Rafaa
authors.initials: R
authors.lastname: Zeineddine
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. jay.pundavela@newcastle.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. jay.pundavela@newcastle.edu.au.
authors.forename: Jay F
authors.initials: JF
authors.lastname: Pundavela
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. lcorcora@uow.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. lcorcora@uow.edu.au.
authors.forename: Lisa
authors.initials: L
authors.lastname: Corcoran
authors.affiliation: Intelligent Polymer Research Institute, University of Wollongong, Wollongong, Australia, 2522. elises@uow.edu.au.
authors.forename: Elise M
authors.initials: EM
authors.lastname: Stewart
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. pddh859@uowmail.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. pddh859@uowmail.edu.au.
authors.forename: Dzung
authors.initials: D
authors.lastname: Do-Ha
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. mcb675@uowmail.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. mcb675@uowmail.edu.au.
authors.forename: Monique
authors.initials: M
authors.lastname: Bax
authors.affiliation: Australian School for Advanced Medicine, Macquarie University, Sydney, Australia, 2109. gilles.guillemin@mq.edu.au.
authors.forename: Gilles
authors.initials: G
authors.lastname: Guillemin
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. kara@uow.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. kara@uow.edu.au.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Vine
authors.affiliation: Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia, 3010. dhatters@unimelb.edu.au.
authors.forename: Danny M
authors.initials: DM
authors.lastname: Hatters
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. heathe@uow.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. heathe@uow.edu.au.
authors.forename: Heath
authors.initials: H
authors.lastname: Ecroyd
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK. cmd44@cam.ac.uk.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia, 3010. bradley.turner@florey.edu.au.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. lezanne@uow.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. lezanne@uow.edu.au.
authors.forename: Lezanne
authors.initials: L
authors.lastname: Ooi
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. mrw@uow.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. mrw@uow.edu.au.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wilson
authors.affiliation: Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, University of British Columbia, Vancouver, Canada, V6T 2B5. Neil.Cashman@vch.ca.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Cashman
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522. jyerbury@uow.edu.au.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522. jyerbury@uow.edu.au.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Yerbury
mesh_terms: D000818:Animals; D002460:Cell Line; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D010873:Pinocytosis / Q000502:physiology*; D066329:Protein Aggregates / Q000502:physiology*; D017510:Protein Folding; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D066329:Protein Aggregates; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1