1. Department of Biological Sciences, Stanford University, Stanford, California 94305, USA
2. PPD Biomarker Discovery Inc., 1505 O'Brien Drive, Menlo Park, California 94025, USA
3. Department of Medical and Molecular Genetics, King's College London School of Medicine, London SE1 9RT, UK

Correspondence to: Ron R. Kopito¹ Correspondence and requests for materials should be addressed to R.R.K. (Email: kopito@stanford.edu).

Abstract

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expansion of CAG triplet repeats in the huntingtin (HTT) gene (also called HD) and characterized by accumulation of aggregated fragments of polyglutamine-expanded HTT protein in affected neurons^{1, 2}. Abnormal enrichment of HD inclusion bodies with ubiquitin, a diagnostic characteristic of HD and many other neurodegenerative disorders including Alzheimer's and Parkinson's diseases^{3, 4}, has suggested that dysfunction in ubiquitin metabolism may contribute to the pathogenesis of these diseases^{5, 6}. Because modification of proteins with polyubiquitin chains regulates many essential cellular processes including protein degradation, cell cycle, transcription, DNA repair and membrane trafficking⁷, disrupted ubiquitin signalling is likely to have broad consequences for neuronal function and survival. Although ubiquitin-dependent protein degradation is impaired in cell-culture models of HD^{8, 9, 10, 11} and of other neurodegenerative diseases^{12, 13}, it has not been possible to evaluate the function of the ubiquitin–proteasome system (UPS) in HD patients or in animal models of the disease, and a functional role for UPS impairment in neurodegenerative disease pathogenesis remains controversial^{14, 15, 16}. Here we exploit a mass-spectrometry-based method to quantify polyubiquitin chains¹⁷ and demonstrate that the abundance of these chains is a faithful endogenous biomarker of UPS function. Lys 48-linked polyubiquitin chains accumulate early in pathogenesis in brains from the R6/2 transgenic mouse model of HD, from a knock-in model of HD and from human HD patients, establishing that UPS dysfunction is a consistent feature of HD pathology. Lys 63- and Lys 11-linked polyubiquitin chains, which are not typically associated with proteasomal targeting, also accumulate in the R6/2 mouse brain. Thus, HD is linked to global changes in the ubiquitin system to a much greater extent than previously recognized.

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