Abnormal platelet aggregation response in Huntington's disease

Muramatsu, Yayoi; Kaiya, Hisanobu; Imai, Hirosato; Nozaki, Masakatsu; Fujimura, Hajimè; Namba, Masashi

doi:10.1007/bf02141780

Cited by 8 publications

(5 citation statements)

References 13 publications

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“…In light of these contradictory findings, we further performed tail bleeding tests in HD mice to evaluate whether thrombosis was indeed affected. Results showed that manifest R6/2 mice bleed less and for shorter periods of time, suggesting that platelets are hyperfunctional and may more readily promote thrombosis, in agreement with the findings described above 47. However, assessment of the cytoarchitecture of blood vessels in the tail of R6/2 mice of the same age (late-stage disease) further revealed important modifications in the vascular network in comparison to WT mice which supports our previous findings of such abnormalities within cerebral tissue 4.…”

Section: Discussionsupporting

confidence: 89%

“…Interestingly, one publication from the 1980s demonstrated that low levels of serotonin can be released from platelets in HD and that the aggregation process of platelets is seemingly impaired 35. Two publications followed up on this and one showed that platelet serotonin levels did not vary in HD,31 while the other demonstrated that platelets were more responsive and therefore aggregated more easily 47. Some antidepressants, such as selective serotonin reuptake inhibitors (SSRI), are responsible for the uptake of serotonin into platelets.…”

Section: Discussionmentioning

confidence: 99%

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Platelet abnormalities in Huntington’s disease

Denis

Lamontagne‐Proulx

St‐Amour

et al. 2018

J Neurol Neurosurg Psychiatry

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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.ObjectivesSeeking 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.MethodsWe 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.ResultsOur 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.ConclusionTaken together, our results provide a better understanding for the impact of mHtt on platelet function.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Platelet abnormalities in Huntington’s disease

Denis

Lamontagne‐Proulx

St‐Amour

et al. 2018

J Neurol Neurosurg Psychiatry

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“…It has been previously described an altered homeostasis of human platelets in HD [25], [26] and an increased density of Adenosine A2a receptor, a protein G-coupled receptor implicated in the regulation of different biochemical processes including the release of NO, in both CNS of transgenic HD mice [13], [27] and blood platelets of patients [5], [6]. However, whether platelets dysfunction contributes to HD pathogenesis, or is an epiphenomenon, remains unclear.…”

Section: Resultsmentioning

confidence: 99%

Nitric Oxide Dysregulation in Platelets from Patients with Advanced Huntington Disease

et al. 2014

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Nitric oxide (NO) is a biologically active inorganic molecule involved in the regulation of many physiological processes, such as control of blood flow, platelet adhesion, endocrine function, neurotransmission and neuromodulation. In the present study, for the first time, we investigated the modulation of NO signaling in platelets of HD patients. We recruited 55 patients with manifest HD and 28 gender- and age-matched healthy controls. Our data demonstrated that NO-mediated vasorelaxation, when evoked by supernatant from insulin-stimulated HD platelets, gradually worsens along disease course. The defective vasorelaxation seems to stem from a faulty release of NO from platelets of HD patients and, it is associated with impairment of eNOS phosphorylation (Ser1177) and activity. This study provides important insights about NO metabolism in HD and raises the hypothesis that the decrease of NO in platelets of HD individuals could be a good tool for monitoring advanced stages of the disease.

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“…Emerging aspects in neurodegenerative processes have been indeed identified at the crossroad between redox homeostasis, tryptophan metabolism as well as inflammation paths and mitochondrial function (Sas et al, 2007;Shukla et al, 2011). Noteworthy, an increased platelet responsiveness to aggregation stimuli was observed in symptomatic patients (Muramatsu et al, 1970) together a blunted NO release in advanced HD (Carrizzo et al, 2014). It seems therefore plausible to assume that platelets change their reactivity in HD, showing BDNF contents that fluctuate dynamically as a function of the progression of the disease and/or administered treatments.…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor (BDNF) and Serotonin Transporter (SERT) in Platelets of Patients with Mild Huntington’s Disease: Relationships with Social Cognition Symptoms

Betti

Palego

Unti³

et al. 2018

Archives Italiennes De Biologie

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Peripheral biological correlates of early-stage Huntington's disease (HD) are currently attracting much interest given their possible use as prognostic predictors of later neurodegeneration.Since deficits in social-cognition processing are present among the initial disease symptoms, aim of this work was to appraise, in blood platelets, Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HT) transporter (SERT), two proteins involved in human adaptive behavior as potential biochemical correlates of such disabilities in mild-HD.Thirteen gene positive and symptomatic patients (9M/4W, HD-stage II, age> 40y) together 11 gender/age matched controls without a concurrent diagnosis of psychiatric disorders, underwent a blood test to determine BDNF storage and membrane-bound SERT in platelets by ELISA immune-enzyme and [ 3 H]-paroxetine ([ 3 H]-PAR) binding assays, respectively. Concomitantly, all subjects were examined through a battery of socio-cognitive and emotion recognition questionnaires.Results showed moderately increased intra-platelet BDNF amounts (+20-22%) in patients versus controls, whereas [ 3 H]-PAR binding parameters, maximum density (Bmax) and dissociation constant (KD), did not appreciably vary between the two groups. While patients displaying significantly reduced cognitive/emotion abilities, biochemical parameters and clinical features or psychosocial scores did not correlate each other, except for platelet BDNF and the illness duration, positively correlated, or for SERT KDs and angry voice recognition ability, negatively correlated in both controls and patients. Therefore, in this pilot investigation, platelet BDNF and SERT did not specifically underlie psychosocial deficits in stage II-HD. Higher platelet BDNF storage in patients showing lasting-mild symptoms would derive from compensatory mechanisms. Thus, supplementary investigations are warranted by also comparing patients in other illness's phases.

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Abnormal platelet aggregation response in Huntington's disease

Cited by 8 publications

References 13 publications

Platelet abnormalities in Huntington’s disease

Platelet abnormalities in Huntington’s disease

Nitric Oxide Dysregulation in Platelets from Patients with Advanced Huntington Disease

Brain-Derived Neurotrophic Factor (BDNF) and Serotonin Transporter (SERT) in Platelets of Patients with Mild Huntington’s Disease: Relationships with Social Cognition Symptoms

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