期刊
MOLECULAR NEURODEGENERATION
卷 10, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s13024-015-0053-4
关键词
Protein aggregation; Transmission; Macropinocytosis
资金
- Australian Postgraduate Award
- PrioNet Canada
- Canadian Institutes of Health Research (CIHR)
- Biogen-Idec Corp.
- ARC
- NHMRC [1003032, 1008910]
- MND Research Institute of Australia Government Operational Infrastructure Support Grant
- MND Research Institute of Victorian Government Operational Infrastructure Support Grant
- NHMRC
- Wellcome Trust
- Motor Neurone Disease Research Institute of Australia
- ARC [FT110100586]
- Australian Research Council [FT110100586] Funding Source: Australian Research Council
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, alpha-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.
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