Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin

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Abstract

Huntington's disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT.

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Tan, Z., Dai, W., Van Erp, T. G. M., Overman, J., Demuro, A., Digman, M. A., … Potkin, S. G. (2015). Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin. Molecular Psychiatry, 20(11), 1286–1293. https://doi.org/10.1038/mp.2015.81

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