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.
|Titolo:||Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin|
|Parole Chiave:||alpha-synuclein; polyglutamine peptides; biomarker changes; mammalian-cells; predict-hd; protein; neurons; repeat; propagation; fragments|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
Settore MED/25 - Psichiatria
|Data di pubblicazione:||nov-2015|
|Digital Object Identifier (DOI):||10.1038/mp.2015.81|
|Appare nelle tipologie:||01 - Articolo su periodico|