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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2015

Open Access 01-12-2015 | Research article

SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

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, Justin J. Yerbury

Published in: Molecular Neurodegeneration | Issue 1/2015

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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.
Appendix
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Metadata
Title
SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation
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
Justin J. Yerbury
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2015
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-015-0053-4

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