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TitleHuntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin.
Journal, issue, pagesMol Psychiatry, Vol. 20, Issue 11, Page 1286-1293, Year 2015
Publish dateJun 23, 2015
AuthorsZ 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 /
PubMed AbstractHuntington'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. ...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.
External linksMol Psychiatry / PubMed:26100538 / PubMed Central
MethodsEM (tomography)
Structure data

EMDB-2991:
Electron cryo-tomography of polyQ seeded mutant huntingtin aggregates from PC12 cells inducibly expressing mHTTex1-GFP
Method: EM (tomography)

Source
  • Rattus norvegicus (Norway rat)

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