SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

Molecular Neurodegeneration

Justin J. Yerbury⁶  Neil R. Cashman⁴  Mark R. Wilson⁶  Lezanne Ooi⁶  Bradley J. Turner³  Christopher M. Dobson⁷  Heath Ecroyd⁶  Danny M. Hatters²  Kara L. Vine⁶  Gilles Guillemin⁵  Monique Bax⁶  Dzung Do-Ha⁶  Elise M. Stewart¹  Lisa Corcoran⁶  Jay F. Pundavela⁶  Rafaa Zeineddine⁶ 

[1] Intelligent Polymer Research Institute, University of Wollongong, Wollongong 2522Australia;Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010Australia;Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010Australia;Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, University of British Columbia, Vancouver V6T 2B5Canada;Australian School for Advanced Medicine, Macquarie University, Sydney 2109Australia;School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong 2522Australia;Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK

关键词: Macropinocytosis;    Transmission;    Protein aggregation;   

Others  :  1230391
DOI  :  10.1186/s13024-015-0053-4

 received in 2015-03-29, accepted in 2015-10-23,  发布年份 2015

【 摘 要 】

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, Htt _ex1 46Q, 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.

【 授权许可】

   
2015 Zeineddine et al.

【 图 表 】

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