Abstract
Protein aggregation and the formation of inclusion bodies are hallmarks of the cytopathology of neurodegenerative diseases, including Huntington's disease, Amyotropic lateral sclerosis, Parkinson's disease and Alzheimer's disease. The cellular toxicity associated with protein aggregates has been suggested to result from the sequestration of essential proteins that are involved in key cellular events, such as transcription, maintenance of cell shape and motility, protein folding and protein degradation. Here, we use fluorescence imaging of living cells to show that polyglutamine protein aggregates are dynamic structures in which glutamine-rich proteins are tightly associated, but which exhibit distinct biophysical interactions. In contrast, the interaction between wild-type, but not mutant, Hsp70 exhibits rapid kinetics of association and dissociation similar to interactions between Hsp70 and thermally unfolded substrates. These studies provide new insights into the composite organization and formation of protein aggregates and show that molecular chaperones are not sequestered into aggregates, but are instead transiently associated.
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Acknowledgements
We thank R. Miller (Northwestern University Medical School) and his laboratory for advice and the use of their microscope facility for FRET analysis, S. Gines and M. MacDonald (Harvard University) for generously sharing reagents, C. Jolly, J. Widom, S. Huang and R. Holmgren for advice and comments on the paper, and use of the Cell Imaging Facilities in the Department of Cell and Molecular Biology at Northwestern Medical School and on the Evanston campus of Northwestern University. These studies were supported by grants to R.M. from the National Institutes of Health (NIGMS 38109), the Huntington Disease Society of America Coalition for the Cure, the Hereditary Disease Foundation, a Mechanisms in Aging and Dementia Training Programme from the National Institutes of Aging to S.K., the Netherlands Organization for Scientific Research and an European Molecular Biology Organization Long-Term Fellowship to E.N.
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Figure S1 Model of the dynamic organization of polyglutamine aggregates. (PDF 290 kb)
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Kim, S., Nollen, E., Kitagawa, K. et al. Polyglutamine protein aggregates are dynamic. Nat Cell Biol 4, 826–831 (2002). https://doi.org/10.1038/ncb863
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DOI: https://doi.org/10.1038/ncb863
