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Platelet abnormalities in Huntington's disease
Hélèna L Denis1,2, Jérôme Lamontagne-Proulx1,2, Isabelle St-Amour1,2
1Centre de Recherche du CHU de Québec, Québec, QC, Canada.
Insights
Platelets in Huntington's disease (HD) are dysfunctional, impacting blood vessel health and function. This study reveals how mutant huntingtin (mHtt) affects platelet function, contributing to HD pathology.
Area of Science:
- Neuroscience
- Genetics
- Vascular Biology
Background:
- Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the huntingtin gene, leading to mutant huntingtin (mHtt) protein accumulation.
- HD brains exhibit vascular abnormalities, including altered blood vessel density and increased blood-brain barrier (BBB) leakage.
- Platelets contain high concentrations of mHtt and play a crucial role in vascular integrity.
Purpose of the Study:
- To investigate the role of platelets in the vascular abnormalities observed in Huntington's disease.
- To elucidate the origin of vascular and BBB abnormalities by studying platelet function in HD patients and a mouse model.
Main Methods:
- Assessed platelet function using ELISA, western blot, and RNA sequencing in 71 HD patients and 68 controls.
- Conducted hemostasis and platelet depletion tests in the R6/2 HD mouse model.
Main Results:
- Platelets from HD patients exhibit dysfunction in releasing angiogenic factors.
- HD platelets show impaired functions related to thrombosis, angiogenesis, and vascular hemostasis.
- Mutant huntingtin (mHtt) significantly impacts platelet function.
Conclusions:
- The study provides a deeper understanding of how mutant huntingtin affects platelet function in Huntington's disease.
- Platelet dysfunction is a key contributor to the vascular pathology in HD.
- Targeting platelet function may offer therapeutic strategies for HD.
Abstract:
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.