Labbadia, J;
Novoselov, SS;
Bett, JS;
Weiss, A;
Paganetti, P;
Bates, GP;
Cheetham, ME;
(2012)
Suppression of protein aggregation by chaperone modification of high molecular weight complexes.
Brain
, 135
(4)
1180 -1196.
10.1093/brain/aws022.
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Abstract
Protein misfolding and aggregation are associated with many neurodegenerative diseases, including Huntington's disease. The cellular machinery for maintaining proteostasis includes molecular chaperones that facilitate protein folding and reduce proteotoxicity. Increasing the protein folding capacity of cells through manipulation of DNAJ chaperones has been shown to suppress aggregation and ameliorate polyglutamine toxicity in cells and flies. However, to date these promising findings have not been translated to mammalian models of disease. To address this issue, we developed transgenic mice that over-express the neuronal chaperone HSJ1a (DNAJB2a) and crossed them with the R6/2 mouse model of Huntington's disease. Over-expression of HSJ1a significantly reduced mutant huntingtin aggregation and enhanced solubility. Surprisingly, this was mediated through specific association with K63 ubiquitylated, detergent insoluble, higher order mutant huntingtin assemblies that decreased their ability to nucleate further aggregation. This was dependent on HSJ1a client binding ability, ubiquitin interaction and functional co-operation with HSP70. Importantly, these changes in mutant huntingtin solubility and aggregation led to improved neurological performance in R6/2 mice. These data reveal that prevention of further aggregation of detergent insoluble mutant huntingtin is an additional level of quality control for late stage chaperone-mediated neuroprotection. Furthermore, our findings represent an important proof of principle that DNAJ manipulation is a valid therapeutic approach for intervention in Huntington's disease.
| Type: | Article |
|---|---|
| Title: | Suppression of protein aggregation by chaperone modification of high molecular weight complexes |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/aws022 |
| Publisher version: | http://dx.doi.org/10.1093/brain/aws022 |
| Language: | English |
| Additional information: | © The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. PMCID: PMC3326252 |
| Keywords: | Age Factors, Analysis of Variance, Animals, Brain, Brain-Derived Neurotrophic Factor, Cell Line, Tumor, Cell Nucleus, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Exploratory Behavior, Gene Expression Regulation, HSP40 Heat-Shock Proteins, Humans, Huntington Disease, Immunoprecipitation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Chaperones, Nerve Tissue Proteins, Neuroblastoma, Neurons, Nuclear Proteins, Protein Folding, Psychomotor Performance, RNA, Messenger, SUMO-1 Protein, Time Factors, Transfection, Trinucleotide Repeats |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1342880 |
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