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dc.contributor.authorDenis, Hélèna L
dc.contributor.authorLamontagne-Proulx, Jérôme
dc.contributor.authorSt-Amour, Isabelle
dc.contributor.authorMason, Sarah
dc.contributor.authorRowley, Jesse W
dc.contributor.authorCloutier, Nathalie
dc.contributor.authorTremblay, Marie-Ève
dc.contributor.authorVincent, Antony T
dc.contributor.authorGould, Peter V
dc.contributor.authorChouinard, Sylvain
dc.contributor.authorWeyrich, Andrew S
dc.contributor.authorRondina, Matthew T
dc.contributor.authorBarker, Roger
dc.contributor.authorBoilard, Eric
dc.contributor.authorCicchetti, Francesca
dc.date.accessioned2019-01-08T00:30:24Z
dc.date.available2019-01-08T00:30:24Z
dc.date.issued2019-03
dc.identifier.issn0022-3050
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287586
dc.description.abstractHuntington's disease (HD) is a hereditary disorder that typically manifests in adulthood with a combination of motor, cognitive and psychiatric problems. The pathology is caused by a mutation in the huntingtin gene which results in the production of an abnormal protein, mutant huntingtin (mHtt). This protein is ubiquitously expressed and known to confer toxicity to multiple cell types. We have recently reported that HD brains are also characterised by vascular abnormalities, which include changes in blood vessel density/diameter as well as increased blood-brain barrier (BBB) leakage. OBJECTIVES: Seeking to elucidate the origin of these vascular and BBB abnormalities, we studied platelets that are known to play a role in maintaining the integrity of the vasculature and thrombotic pathways linked to this, given they surprisingly contain the highest concentration of mHtt of all blood cells. METHODS: We assessed the functional status of platelets by performing ELISA, western blot and RNA sequencing in a cohort of 71 patients and 68 age- and sex-matched healthy control subjects. We further performed haemostasis and platelet depletion tests in the R6/2 HD mouse model. RESULTS: Our findings indicate that the platelets in HD are dysfunctional with respect to the release of angiogenic factors and functions including thrombosis, angiogenesis and vascular haemostasis. CONCLUSION: Taken together, our results provide a better understanding for the impact of mHtt on platelet function.
dc.description.sponsorshipFunding sources: The study was funded by a grant program of the Faculty of Medicine of Université Laval from Merck Sharpe & Dohme Corp to F.C. F.C. who is also a recipient of a Researcher Chair from the Fonds de Recherche du Québec en santé (FRQS) providing salary support and operating funds. I.S.-A. was supported by a CIHR-Huntington Society of Canada postdoctoral fellowship. R.A.B. and S.L.M. are supported by a National Institute for Health Research (NIHR) award of a Biomedical Research Center to the University of Cambridge and Addenbrooke’s Hospital. H.L.D and J.P.L hold a Desjardins scholarship from the Fondation du CHU de Québec. HLD hold a bourse d’excellence du Centre Thématique de Recherche en Neurosciences (CTRN) du CHU de Québec. E.B. is supported by the Canadian Institutes of Health Research. The RNA-seq work was supported by the NHLBI and NIA (HL112311 and HL126547 to M.T.R. and AG048022 to M.T.R.). This material is the result of work supported with resources and the use of facilities at the George E. Wahlen VA Medical Center, Salt Lake City, Utah. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherBMJ
dc.rightsAttribution-NonCommercial 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.subjectBlood-Brain Barrier
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectHuntington Disease
dc.subjectDisease Models, Animal
dc.subjectAngiogenic Proteins
dc.subjectFibroblast Growth Factor 2
dc.subjectBlood Coagulation Factors
dc.subjectPlatelet Count
dc.subjectCase-Control Studies
dc.subjectCohort Studies
dc.subjectPlatelet Activation
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectHuntingtin Protein
dc.titlePlatelet abnormalities in Huntington's disease.
dc.typeArticle
prism.endingPage283
prism.issueIdentifier3
prism.publicationDate2019
prism.publicationNameJ Neurol Neurosurg Psychiatry
prism.startingPage272
prism.volume90
dc.identifier.doi10.17863/CAM.34899
dcterms.dateAccepted2018-09-24
rioxxterms.versionofrecord10.1136/jnnp-2018-318854
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-03
dc.contributor.orcidMason, Sarah [0000-0001-6715-4109]
dc.contributor.orcidBarker, Roger [0000-0001-8843-7730]
dc.identifier.eissn1468-330X
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-12-19


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Attribution-NonCommercial 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial 4.0 International