Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients
Identifieur interne : 000567 ( Main/Exploration ); précédent : 000566; suivant : 000568Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients
Auteurs : Edward J. Wild [Royaume-Uni] ; Roberto Boggio [Italie] ; Douglas Langbehn [États-Unis] ; Nicola Robertson [Royaume-Uni] ; Salman Haider [Royaume-Uni] ; James R. C. Miller [Royaume-Uni] ; Henrik Zetterberg [Royaume-Uni, Suède] ; Blair R. Leavitt [Canada] ; Rainer Kuhn [Italie] ; Sarah J. Tabrizi [Royaume-Uni] ; Douglas Macdonald [États-Unis] ; Andreas Weiss [Italie]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2015.
Abstract
Url:
DOI: 10.1172/JCI80743
PubMed: 25844897
PubMed Central: 4463213
Affiliations:
- Canada, Italie, Royaume-Uni, Suède, États-Unis
- Angleterre, Californie, Grand Londres, Iowa
- Iowa City, Londres
- University College de Londres, Université de l'Iowa
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Le document en format XML
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<series><title level="j">The Journal of Clinical Investigation</title>
<idno type="ISSN">0021-9738</idno>
<idno type="eISSN">1558-8238</idno>
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<front><div type="abstract" xml:lang="en"><p><bold>BACKGROUND</bold>
: 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.</p>
<p><bold>METHODS</bold>
: 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.</p>
<p><bold>RESULTS</bold>
: 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.</p>
<p><bold>CONCLUSIONS</bold>
: 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.</p>
<p><bold>TRIAL REGISTRATION</bold>
: Not applicable.</p>
<p><bold>FUNDING</bold>
: CHDI Foundation Inc.; Medical Research Council (MRC) UK; National Institutes for Health Research (NIHR); Rosetrees Trust; Swedish Research Council; and Knut and Alice Wallenberg Foundation.</p>
</div>
</front>
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<name sortKey="Kuhn, Rainer" sort="Kuhn, Rainer" uniqKey="Kuhn R" first="Rainer" last="Kuhn">Rainer Kuhn</name>
<name sortKey="Weiss, Andreas" sort="Weiss, Andreas" uniqKey="Weiss A" first="Andreas" last="Weiss">Andreas Weiss</name>
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<country name="États-Unis"><region name="Iowa"><name sortKey="Langbehn, Douglas" sort="Langbehn, Douglas" uniqKey="Langbehn D" first="Douglas" last="Langbehn">Douglas Langbehn</name>
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<name sortKey="Macdonald, Douglas" sort="Macdonald, Douglas" uniqKey="Macdonald D" first="Douglas" last="Macdonald">Douglas Macdonald</name>
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<country name="Suède"><noRegion><name sortKey="Zetterberg, Henrik" sort="Zetterberg, Henrik" uniqKey="Zetterberg H" first="Henrik" last="Zetterberg">Henrik Zetterberg</name>
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<country name="Canada"><noRegion><name sortKey="Leavitt, Blair R" sort="Leavitt, Blair R" uniqKey="Leavitt B" first="Blair R." last="Leavitt">Blair R. Leavitt</name>
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