Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin

被引：0
作者：
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
机构：
[1] Institute for Memory Impairment and Neurological Disorders,Verna and Marrs McLean Department of Biochemistry and Molecular Biology
[2] University of California-Irvine,Department of Psychiatry and Human Behavior
[3] Baylor College of Medicine,Department of Neurobiology and Behavior
[4] University of California-Irvine,Department of Biomedical Engineering
[5] University of California-Irvine,Department of Molecular Biology and Biochemistry
[6] Laboratory for Fluorescence Dynamics,Department of Psychiatry
[7] University of California-Irvine,Department of Biostatistics
[8] University of California,Department of Neurology and Psychology
[9] University of Iowa,Department of Neurology
[10] University of Iowa,Department of Biochemistry
[11] University of Iowa,undefined
[12] Easton Center for Alzheimer’s Disease Research,undefined
[13] University of California-Los Angeles,undefined
[14] Faculty of Science and Experimental Biochemistry Unit,undefined
[15] King Fahd Medical Research Center,undefined
[16] King Abdulaziz University,undefined
[17] 12Current address: Department of Neurology,undefined
[18] David Geffen School of Medicine,undefined
[19] University of California-Los Angeles,undefined
[20] Los Angeles,undefined
[21] CA,undefined
[22] USA.,undefined
[23] 13Current address: Department of Biology,undefined
[24] Stanford University,undefined
[25] Stanford,undefined
[26] CA,undefined
[27] USA.,undefined
来源：
Molecular Psychiatry | 2015年 / 20卷
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摘要：
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.
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页码：1286 / 1293
页数：7
相关论文
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