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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)
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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. Conclusion: 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.

Original languageEnglish
Article number57
Pages (from-to)1-17
Number of pages17
JournalMolecular Neurodegeneration
Volume10
DOIs
Publication statusPublished - 31 Oct 2015

Bibliographical note

Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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