Journal article
Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients
The Journal of clinical investigation, Vol.125(5), pp.1979-1986
05/01/2015
DOI: 10.1172/JCI80743
PMCID: PMC4463213
PMID: 25844897
Abstract
BACKGROUND: Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously.
METHODS: We developed an ultrasensitive single-molecule counting (SMC) mHTT immunoassay that was used to quantify mHTT levels in CSF samples from individuals bearing the HD mutation and from control individuals in 2 independent cohorts.
RESULTS: This SMC mHTT immunoassay demonstrated high specificity for mHTT, high sensitivity with a femtomolar detection threshold, and a broad dynamic range. Analysis of the CSF samples showed that mHTT was undetectable in CSF from all controls but quantifiable in nearly all mutation carriers. The mHTT concentration in CSF was approximately 3-fold higher in patients with manifest HD than in premanifest mutation carriers. Moreover, mHTT levels increased as the disease progressed and were associated with 5-year onset probability. The mHTT concentration independently predicted cognitive and motor dysfunction. Furthermore, the level of mHTT was associated with the concentrations of tau and neurofilament light chain in the CSF, suggesting a neuronal origin for the detected mHTT.
CONCLUSIONS: We have demonstrated that mHTT can be quantified in CSF from HD patients using the described SMC mHTT immunoassay. Moreover, the level of mHTT detected is associated with proximity to disease onset and diminished cognitive and motor function. The ability to quantify CSF mHTT will facilitate the study of HD, and mHTT quantification could potentially serve as a biomarker for the development and testing of experimental mHTT-lowering therapies for HD.
Details
- Title: Subtitle
- Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients
- Creators
- Edward J. Wild - UCL, Inst Neurol, Natl Hosp Neurol & Neurosurg, London, EnglandRoberto Boggio - SRLDouglas Langbehn - Univ Iowa, Carver Coll Med, Iowa City, IA USANicola Robertson - UCL, Inst Neurol, Natl Hosp Neurol & Neurosurg, London, EnglandSalman Haider - UCL, Inst Neurol, Natl Hosp Neurol & Neurosurg, London, EnglandJames R. C. Miller - UCL, Inst Neurol, Natl Hosp Neurol & Neurosurg, London, EnglandHenrik Zetterberg - Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, SwedenBlair R. Leavitt - Univ British Columbia, Dept Med Genet, Ctr Mol Med & Therapeut, Vancouver, BC, CanadaRainer Kuhn - SRLSarah J. Tabrizi - UCL, Inst Neurol, Natl Hosp Neurol & Neurosurg, London, EnglandDouglas Macdonald - CHDI Management CHDI Fdn, Los Angeles, CA 90045 USAAndreas Weiss - SRL
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.125(5), pp.1979-1986
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/JCI80743
- PMID
- 25844897
- PMCID
- PMC4463213
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Number of pages
- 8
- Grant note
- CL-2009-18-005 / National Institute for Health Research; National Institute for Health Research (NIHR) National Institutes for Health Research (NIHR) Rosetrees Trust Swedish Research Council; European Commission 1354752 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission M220 / Rosetrees Trust Medical Research Council (MRC) UK; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) MR/M008592/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Knut and Alice Wallenberg Foundation; Knut & Alice Wallenberg Foundation CHDI Foundation Inc.
- Language
- English
- Date published
- 05/01/2015
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984293652502771
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