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.
Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin / Z. Tan, W. Dai, T.G.M. van Erp, J. Overman, A. Demuro, M.A. Digman, A. Hatami, R. Albay, E.M. Sontag, K.T. Potkin, S. Ling, F. Macciardi, W.E. Bunney, J.D. Long, J.S. Paulsen, J.M. Ringman, I. Parker, C. Glabe, L.M. Thompson, W. Chiu, S.G. Potkin. - In: MOLECULAR PSYCHIATRY. - ISSN 1359-4184. - 20:11(2015 Nov), pp. 1286-1293. [10.1038/mp.2015.81]
Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin
F. Macciardi;
2015
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.File | Dimensione | Formato | |
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