title: Suppression of protein aggregation by chaperone modification of high molecular weight complexes.
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.
authors.affiliation: Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, UK.
authors.forename: John
authors.initials: J
authors.lastname: Labbadia
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Novoselov
authors.forename: John S
authors.initials: JS
authors.lastname: Bett
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005106:Exploratory Behavior / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C121958:DNAJB2 protein, human; D050956:HSP40 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D025842:SUMO-1 Protein