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Mol Psychiatry. 2015 Nov;20(11):1286-93. doi: 10.1038/mp.2015.81. Epub 2015 Jun 23.

Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin.

Author information

1
Institute for Memory Impairment and Neurological Disorders, University of California-Irvine, Irvine, CA, USA.
2
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
3
Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
4
Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
5
Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California-Irvine, Irvine, CA, USA.
6
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
7
Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
8
Department of Biostatistics, University of Iowa, Iowa City, IA, USA.
9
Department of Neurology and Psychology, University of Iowa, Iowa City, IA, USA.
10
Department of Neurology, Easton Center for Alzheimer's Disease Research, University of California-Los Angeles, Los Angeles, CA, USA.
11
Faculty of Science and Experimental Biochemistry Unit, Department of Biochemistry, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

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.

PMID:
26100538
PMCID:
PMC4718563
DOI:
10.1038/mp.2015.81
[Indexed for MEDLINE]
Free PMC Article

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