title: Mutant huntingtin fragmentation in immune cells tracks Huntington's disease progression.
abstract: Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Therapeutic approaches to lower mutant HTT (mHTT) levels are expected to proceed to human trials, but noninvasive quantification of mHTT is not currently possible. The importance of the peripheral immune system in neurodegenerative disease is becoming increasingly recognized. Peripheral immune cells have been implicated in HD pathogenesis, but HTT levels in these cells have not been quantified before. A recently described time-resolved Förster resonance energy transfer (TR-FRET) immunoassay was used to quantify mutant and total HTT protein levels in leukocytes from patients with HD. Mean mHTT levels in monocytes, T cells, and B cells differed significantly between patients with HD and controls and between pre-manifest mutation carriers and those with clinical onset. Monocyte and T cell mHTT levels were significantly associated with disease burden scores and caudate atrophy rates in patients with HD. mHTT N-terminal fragments detected in HD PBMCs may explain the progressive increase in mHTT levels in these cells. These findings indicate that quantification of mHTT in peripheral immune cells by TR-FRET holds significant promise as a noninvasive disease biomarker.
authors.affiliation: Neuroscience Discovery, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.forename: Ulrike
authors.initials: U
authors.lastname: Träger
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Wild
authors.forename: Stephan
authors.initials: S
authors.lastname: Grueninger
authors.forename: Ruth
authors.initials: R
authors.lastname: Farmer
authors.forename: Christian
authors.initials: C
authors.lastname: Landles
authors.forename: Rachael I
authors.initials: RI
authors.lastname: Scahill
authors.forename: Nayana
authors.initials: N
authors.lastname: Lahiri
authors.forename: Salman
authors.initials: S
authors.lastname: Haider
authors.forename: Douglas
authors.initials: D
authors.lastname: Macdonald
authors.forename: Chris
authors.initials: C
authors.lastname: Frost
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.forename: Graeme
authors.initials: G
authors.lastname: Bilbe
authors.forename: Rainer
authors.initials: R
authors.lastname: Kuhn
authors.forename: Ralph
authors.initials: R
authors.lastname: Andre
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
mesh_terms: D001284:Atrophy; D001402:B-Lymphocytes / Q000737:chemistry*; D015415:Biomarkers; D015153:Blotting, Western; D002421:Caudate Nucleus / Q000473:pathology; D018450:Disease Progression; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000097:blood* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D047468:Immunoprecipitation; D007962:Leukocytes / Q000737:chemistry*; D009000:Monocytes / Q000737:chemistry*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000097:blood* / Q000235:genetics; D013601:T-Lymphocytes / Q000737:chemistry*
chemical_list: D015415:Biomarkers; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins