Journal article
Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin
Molecular psychiatry, Vol.20(11), pp.1286-1293
11/2015
DOI: 10.1038/mp.2015.81
PMCID: PMC4718563
PMID: 26100538
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.
Details
- Title: Subtitle
- Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin
- Creators
- Z Tan - University of California, IrvineW Dai - Baylor College of MedicineT G M van Erp - University of California, IrvineJ Overman - University of California, IrvineA Demuro - University of California, IrvineM A Digman - University of California, IrvineA Hatami - University of California, Los AngelesR Albay - University of California, IrvineE M Sontag - Stanford UniversityK T Potkin - University of California, IrvineS Ling - University of California, IrvineF Macciardi - University of California, IrvineW E Bunney - University of California, IrvineJ D Long - University of IowaJ S Paulsen - University of IowaJ M Ringman - University of California, Los AngelesI Parker - University of California, IrvineC Glabe - King Abdulaziz UniversityL M Thompson - University of California, IrvineW Chiu - Baylor College of MedicineS G Potkin - University of California, Irvine
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.20(11), pp.1286-1293
- DOI
- 10.1038/mp.2015.81
- PMID
- 26100538
- PMCID
- PMC4718563
- NLM abbreviation
- Mol Psychiatry
- ISSN
- 1359-4184
- eISSN
- 1476-5578
- Grant note
- R01 NS040068 / NINDS NIH HHS U24 RR021992 / NCRR NIH HHS 5P41GM10383229 / NIGMS NIH HHS 5U24RR021992 / NCRR NIH HHS 5P50AG016570 / NIA NIH HHS PN2 EY016525 / NEI NIH HHS P50 GM076516 / NIGMS NIH HHS 1U01NS087825 / NINDS NIH HHS P50 AG016570 / NIA NIH HHS 5R01NS040068 / NINDS NIH HHS 5PN2EY016525 / NEI NIH HHS P41 GM103832 / NIGMS NIH HHS U01 NS087825 / NINDS NIH HHS 5R37GM048071 / NIGMS NIH HHS R37 GM048071 / NIGMS NIH HHS PN1 EY016525 / NEI NIH HHS
- Language
- English
- Date published
- 11/2015
- Academic Unit
- Psychiatry; Psychological and Brain Sciences; Biostatistics
- Record Identifier
- 9984280842302771
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