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Platelet-derived extracellular vesicles in Huntington’s disease

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Abstract

The production and release of extracellular vesicles (EV) is a property shared by all eukaryotic cells and a phenomenon frequently exacerbated in pathological conditions. The protein cargo of EV, their cell type signature and availability in bodily fluids make them particularly appealing as biomarkers. We recently demonstrated that platelets, among all types of blood cells, contain the highest concentrations of the mutant huntingtin protein (mHtt)—the genetic product of Huntington’s disease (HD), a neurodegenerative disorder which manifests in adulthood with a complex combination of motor, cognitive and psychiatric deficits. Herein, we used a cohort of 59 HD patients at all stages of the disease, including individuals in pre-manifest stages, and 54 healthy age- and sex-matched controls, to evaluate the potential of EV derived from platelets as a biomarker. We found that platelets of pre-manifest and manifest HD patients do not release more EV even if they are activated. Importantly, mHtt was not found within EV derived from platelets, despite them containing high levels of this protein. Correlation analyses also failed to reveal an association between the number of platelet-derived EV and the age of the patients, the number of CAG repeats, the Unified Huntington Disease Rating Scale total motor score, the Total Functional Capacity score or the Burden of Disease score. Our data would, therefore, suggest that EV derived from platelets with HD is not a valuable biomarker in HD.

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Acknowledgements

The study was funded by an operating grant from the Merck Sharpe & Dohme to F. C. who is also a recipient of a Research 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. E. B. is supported by the Canadian Institutes of Health Research. N. D. MD-MSc. also funded by CIHR and by Canadian Consortium on Neurodegeneration in Aging (CCNA). HLD and JPL 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. The authors would like to thank all the students and staff who helped with the blood collections in Cambridge, Quebec City and Montreal and importantly, all patients and their families for being so generous with their time for participating in this study.

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  1. Hélèna L. Denis and Jérôme Lamontagne-Proulx contributed equally to this work.

Authors and Affiliations

  1. Centre de Recherche du CHU de Québec, Québec, QC, Canada

    Hélèna L. Denis, Jérôme Lamontagne-Proulx, Isabelle St-Amour, Eric Boilard & Francesca Cicchetti

  2. Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK

    Sarah L. Mason & Roger A. Barker

  3. Evotec AG, Manfred Eigen Campus, Hamburg, Germany

    Andreas Weiss

  4. Centre Hospitalier de l’Université de Montréal et Centre de recherche du Centre Hospitalier de l’Université de Montréal, Département de médecine, Hôpital Notre-Dame, Université de Montréal, Montréal, QC, Canada

    Sylvain Chouinard

  5. Département de microbiologie-infectiologie et d’immunologie, Université Laval, Québec, QC, Canada

    Eric Boilard

  6. Département de psychiatrie et neurosciences, Université Laval, Québec, QC, Canada

    Francesca Cicchetti

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Contributions

HLD participated in experiments, data analysis/interpretation and preparation of figures. She wrote the first draft of the manuscript and helped with subsequent revisions. JLP participated in the design of the experiments and various aspects of the study including blood collections, experiments and data analysis. IS-A participated in the design of the experiments and blood collections, took part in some data analysis and interpretation. SLM helped with patient recruitment in Cambridge and participated in the preparation of blood collection. AW performed T-FRET analyses related to Fig. 1i. SC recruited patients in Montreal. RAB recruited patients in Cambridge, participated in data interpretation and revised the manuscript. EB initiated the study and was involved in the experimental design. He also revised the manuscript. FC initiated the study and was involved in the experimental design. She supervised the project and wrote the manuscript.

Corresponding authors

Correspondence to Eric Boilard or Francesca Cicchetti.

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Electronic supplementary material

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415_2018_9022_MOESM1_ESM.pdf

Supplementary material 1 Figure S1. Identified biomarkers in HD. Summary of the literature for all reported biomarkers of HD in CSF, blood, urine and brain. Abbreviations: DOPA: 3,4-dihydroxyphenylalanine; DOPAC: 3,4-dihydroxyphenylacetic acid; IL-6: Interleukin 6;IL-8: Interleukin 8; NMDA: N-methyl-D-aspartate; mHtt: mutant huntingtin; Cu/Zn-SOD: Cu/Zn Superoxide Dismutase; HD: Huntington disease; PCYT1A: Phosphate Cytidylyltransferase 1, Pre-HD : pre-manifest, Choline, Alpha; YKL-40: chitinase-like protein-40; 5-HIAA: 5-hydroxyindoleacetic acid; 8-OHdG: 8-hydroxy-2’ -deoxyguanosine; 8-oxodG6: 8-oxo-7,8-dihydro-2′-deoxyguanosine; ↑ ; increase; ↓; decrease; ✔; presence (PDF 13620 KB)

415_2018_9022_MOESM2_ESM.pdf

Supplementary material 2 Figure S2. (A) Absence of statistical differences in comorbidities of healthy control patients - which including depression (p=0.2455), diabetes (p=0.0749), hypertension (p=0.9664), hypercholesterolemia (p=0.3615), allergies (p=0.9904) and anxiety (p=0.4675) - and counts of EV derived from platelets. EV from patients without comorbidities were further compared to patients with one or more comorbidities. Again, no statistically significant differences were found (p=0.6745). Statistical analyses were performed using the non-parametric Mann Whitney test. (B) Immunoblot of CD41a, ALIX, TSG101, actin and VDAC in platelet-derived EV or plts. Data are representative of 3 independent experiments. (C) Left panel: After the acquisition of fluorescent signals, an initial gating was performed on all data to exclude counting beads from files. In this experiment, 144 beads were counted. Right panel: Representation of SSC-H (granularity) and FSC-PMT-H (relative size) dot plots of platelet-derived EV in PFP detecting using PerCP-CyTM5.5-conjugated annexin V and V450-conjugated antibodies directed against CD41. The size of platelet-derived EV ranged between 100 and 1000nm. Abbreviations: ALIX, programmed cell death 6 interacting protein; EV, extracellular vesicles; plts, platelets; TSG101, tumor susceptibility gene 101 protein; VDAC, Voltage-dependent anion-selective channel 1 (PDF 1813 KB)

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Denis, H.L., Lamontagne-Proulx, J., St-Amour, I. et al. Platelet-derived extracellular vesicles in Huntington’s disease. J Neurol 265, 2704–2712 (2018). https://doi.org/10.1007/s00415-018-9022-5

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