Huntington’s Disease Cerebrospinal Fluid Seeds Aggregation of Mutant Huntingtin

Authors

Z. Tan, University of California - Irvine
W. Dai, Baylor College of Medicine
Theo G.M. van Erp, University of California - Irvine
J. Overman, University of California - Irvine
A. Demuro, University of California - Irvine
M. A. Digman, University of California - Irvine
A. Hatami, University of California - Irvine
R. Albay, University of California - Irvine
Emily M. Sontag, Marquette UniversityFollow
K. T. Potkin, University of California - Irvine
S. Ling, University of California - Irvine
F. Macciardi, University of California - Irvine
W. E. Bunney, University of California - Irvine
J. D. Long, University of Iowa
J. S. Paulsen, University of Iowa
J. M. Ringman, University of California - Los Angeles
I. Parker, University of California - Irvine
Charles G. Glabe, University of California - Irvine
L. M. Thompson, University of California - Irvine
W. Chiu, Baylor College of Medicine
Steven G. Potkin, University of California - Irvine

Document Type

Article

Publication Date

11-2015

Publisher

Springer

Source Publication

Molecular Psychiatry

Source ISSN

1359-4184

Original Item ID

DOI: 10.1038/mp.2015.81

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.

Comments

Accepted version. Molecular Psychiatry, Vol. 20 (2015): 1286-1293. DOI. © 2015 Springer. Used with permission.

Recommended Citation

Tan, Z.; Dai, W.; van Erp, Theo G.M.; Overman, J.; Demuro, A.; Digman, M. A.; Hatami, A.; Albay, R.; Sontag, Emily M.; Potkin, K. T.; Ling, S.; Macciardi, F.; Bunney, W. E.; Long, J. D.; Paulsen, J. S.; Ringman, J. M.; Parker, I.; Glabe, Charles G.; Thompson, L. M.; Chiu, W.; and Potkin, Steven G., "Huntington’s Disease Cerebrospinal Fluid Seeds Aggregation of Mutant Huntingtin" (2015). Biological Sciences Faculty Research and Publications. 939.
https://epublications.marquette.edu/bio_fac/939