SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation |
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| Authors: | Rafaa?Zeineddine Jay?F?Pundavela Lisa?Corcoran Elise?M?Stewart Dzung?Do-Ha Monique?Bax Gilles?Guillemin Kara?L?Vine Danny?M?Hatters Heath?Ecroyd Christopher?M?Dobson Bradley?J?Turner Lezanne?Ooi Mark?R?Wilson Neil?R?Cashman Email author" target="_blank">Justin?J?YerburyEmail author |
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| Institution: | 1.Illawarra Health and Medical Research Institute,Wollongong,Australia;2.School of Biological Sciences, Faculty of Science, Medicine and Health,University of Wollongong,Wollongong,Australia;3.Intelligent Polymer Research Institute, University of Wollongong,Wollongong,Australia;4.Australian School for Advanced Medicine,Macquarie University,Sydney,Australia;5.Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute,University of Melbourne,Parkville,Australia;6.Department of Chemistry,University of Cambridge,Cambridge,UK;7.Florey Institute of Neuroscience and Mental Health,University of Melbourne,Parkville,Australia;8.Department of Medicine (Neurology),University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, University of British Columbia,Vancouver,Canada |
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| Abstract: | BackgroundAmyotrophic 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.ResultsWe 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.ConclusionThus, 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. |
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