This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. An effective therapy for late-onset neurodegenerative diseases remains elusive. These disorders are often associated with the accumulation of insoluble amyloid aggregates, and subsequent neuronal dysfunction and death. In many cases, such as Spinocerebellar Ataxia and Huntington's disease (HD), aggregation is associated with expanded polyglutamine (polyQ) tracts in the disease gene, usually beyond a critical threshold of approximately 40 glutamine repeats. Molecular chaperones, which selectively bind non-native proteins and facilitate their folding or degradation, have been shown to modulate aggregation and toxicity in neurodegenerative disease models. Recently, Frydman found that the eukaryotic chaperonin TRiC/CCT controls polyglutamine aggregation and toxicity in vivo and acts as a potent inhibitor of aggregation. Strikingly, we found that TRiC subunit CCT1, and more specifically the 140 amino acid CCT1 apical domain, directly inhibits the aggregation and neurotoxicity associated with the causative agent of Huntington's disease (polyglutamine-expanded huntingtin exon1). We propose to use cryoEM to study the morphology of the Huntingtin firbils which are grown at different times and see the aggregation upon treatment with TRiC.
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