title: Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin.
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.
authors.affiliation: Institute for Memory Impairment and Neurological Disorders, University of California-Irvine, Irvine, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: T G M
authors.initials: TG
authors.lastname: van Erp
authors.affiliation: Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Overman
authors.affiliation: Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Demuro
authors.affiliation: Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California-Irvine, Irvine, CA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Digman
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Hatami
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Albay
authors.affiliation: Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Sontag
authors.affiliation: Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Potkin
authors.affiliation: Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ling
authors.affiliation: Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Macciardi
authors.affiliation: Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Bunney
authors.affiliation: Department of Psychiatry, University of Iowa, Iowa City, IA, USA.|Department of Biostatistics, University of Iowa, Iowa City, IA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Long
authors.affiliation: Department of Psychiatry, University of Iowa, Iowa City, IA, USA.|Department of Neurology and Psychology, University of Iowa, Iowa City, IA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Paulsen
authors.affiliation: Department of Neurology, Easton Center for Alzheimer's Disease Research, University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Ringman
authors.affiliation: Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Parker
authors.affiliation: Institute for Memory Impairment and Neurological Disorders, University of California-Irvine, Irvine, CA, USA.|Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.|Faculty of Science and Experimental Biochemistry Unit, Department of Biochemistry, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: C
authors.initials: C
authors.lastname: Glabe
authors.affiliation: Institute for Memory Impairment and Neurological Disorders, University of California-Irvine, Irvine, CA, USA.|Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.|Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Thompson
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chiu
authors.affiliation: Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Potkin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010455:Peptides / Q000134:cerebrospinal fluid*; D066263:Protein Aggregation, Pathological / Q000134:cerebrospinal fluid* / Q000473:pathology; D051381:Rats; D055647:Rats, Transgenic; D014162:Transfection
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine