Journal article

SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

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, Justin J Yerbury



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-sy..

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Awarded by NHMRC

Awarded by ARC

Funding Acknowledgements

RZ is supported by an Australian Postgraduate Award. NRC is supported by donations from the Allen T. Lambert Neural Research Fund and the Temerty Family Foundation, and also by grants from PrioNet Canada, the Canadian Institutes of Health Research (CIHR), and Biogen-Idec Corp. JJY is supported by an ARC Discovery Early Career Award, and by NHMRC project grant 1003032. BJT is supported by NHMRC Project Grant 1008910, MND Research Institute of Australia and Victorian Government's Operational Infrastructure Support Grant. DMH is supported by an ARC Future Fellowship and NHMRC project grants. CMD is supported by the Wellcome Trust. LO is supported by an NHMRC project grant and the Motor Neurone Disease Research Institute of Australia. NRC declares that he is Founder, Chief Scientific Officer and Chairman of Amorfix Life Sciences. HE is supported by an ARC Future Fellowship (FT110100586).