title: Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression.
abstract: Quantitation of huntingtin protein in the brain is needed, both as a marker of Huntington disease (HD) progression and for use in clinical gene silencing trials. Measurement of huntingtin in cerebrospinal fluid could be a biomarker of brain huntingtin, but traditional protein quantitation methods have failed to detect huntingtin in cerebrospinal fluid. Using micro-bead based immunoprecipitation and flow cytometry (IP-FCM), we have developed a highly sensitive mutant huntingtin detection assay. The sensitivity of huntingtin IP-FCM enables accurate detection of mutant huntingtin protein in the cerebrospinal fluid of HD patients and model mice, demonstrating that mutant huntingtin levels in cerebrospinal fluid reflect brain levels, increasing with disease stage and decreasing following brain huntingtin suppression. This technique has potential applications as a research tool and as a clinical biomarker.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4; Canada.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Southwell
authors.affiliation: Mayo Clinic College of Medicine, Department of Immunology, Rochester, MN 55905.
authors.forename: Stephen E P
authors.initials: SE
authors.lastname: Smith
authors.affiliation: Mayo Clinic College of Medicine, Department of Immunology, Rochester, MN 55905.
authors.forename: Tessa R
authors.initials: TR
authors.lastname: Davis
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4; Canada.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Caron
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4; Canada.
authors.forename: Erika B
authors.initials: EB
authors.lastname: Villanueva
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4; Canada.
authors.forename: Yuanyun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4; Canada.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Collins
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4; Canada.
authors.forename: Min Li
authors.initials: ML
authors.lastname: Ye
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4; Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Sturrock
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4; Canada.
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.affiliation: Mayo Clinic College of Medicine, Department of Immunology, Rochester, MN 55905.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Schrum
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4; Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D012720:Severity of Illness Index
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins