Platelet abnormalities in Huntington's disease.

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Denis, Hélèna L 
Lamontagne-Proulx, Jérôme 
St-Amour, Isabelle 
Mason, Sarah L 
Rowley, Jesse W 

UNLABELLED: Huntington'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.

Adult, Aged, Angiogenic Proteins, Animals, Blood Coagulation Factors, Blood-Brain Barrier, Case-Control Studies, Cohort Studies, Disease Models, Animal, Female, Fibroblast Growth Factor 2, Humans, Huntingtin Protein, Huntington Disease, Male, Mice, Middle Aged, Platelet Activation, Platelet Count
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J Neurol Neurosurg Psychiatry
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Funding 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.