Levodopa partially rescues microglial numerical, morphological, and phagolysosomal alterations in a monkey model of Parkinson's disease

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dc.contributor.authorLecours, Cynthia
dc.contributor.authorSt-Pierre, Marie-Kim
dc.contributor.authorPicard, Katherine
dc.contributor.authorBordeleau, Maude
dc.contributor.authorBourque, Melanie
dc.contributor.authorAwogbindin, Ifeoluwa Oluleke
dc.contributor.authorBenadjal, Amin
dc.contributor.authorGonzález Ibanez, Fernando
dc.contributor.authorGagnon, Dave
dc.contributor.authorCantin, Leo
dc.contributor.authorParent, Martin
dc.contributor.authorDi Paolo, Therese
dc.contributor.authorTremblay, Marie-Ève
dc.date.accessioned2020-10-19T22:16:25Z
dc.date.available2020-10-19T22:16:25Z
dc.date.copyright2020en_US
dc.date.issued2020
dc.description.abstractParkinson’s disease (PD) is the most common neurodegenerative motor disorder. The mechanisms underlying the onset and progression of Levodopa (L-Dopa)-induced dyskinesia (LID) during PD treatment remain elusive. Emerging evidence implicates functional modification of microglia in the development of LID. Thus, understanding the link between microglia and the development of LID may provide the knowledge required to preserve or promote beneficial microglial functions, even during a prolonged L-Dopa treatment. To provide novel insights into microglial functional alterations in PD pathophysiology, we characterized their density, morphology, ultrastructure, and degradation activity in the sensorimotor functional territory of the putamen, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cynomolgus monkeys. A subset of MPTP monkeys was treated orally with L-Dopa and developed LID similar to PD patients. Using a combination of light, confocal and transmission electron microscopy, our quantitative analyses revealed alterations of microglial density, morphology and phagolysosomal activity following MPTP intoxication that were partially normalized with L-Dopa treatment. In particular, microglial density, cell body and arborization areas were increased in the MPTP monkeys, whereas L-Dopa-treated MPTP animals presented a microglial phenotype similar to the control animals. At the ultrastructural level, microglia did not differ between groups in their markers of cellular stress or aging. Nevertheless, microglia from the MPTP monkeys displayed reduced numbers of endosomes, compared with control animals, that remained lower after L-Dopa treatment. Microglia from MPTP monkeys treated with L-Dopa also had increased numbers of primary lysosomes compared with non-treated MPTP animals, while secondary and tertiary lysosomes remained unchanged. Moreover, a decrease microglial immunoreactivity for CD68, considered a marker of phagocytosis and lysosomal activity, was measured in the MPTP monkeys treated with L-Dopa, compared with non-treated MPTP animals. Taken together, these findings revealed significant changes in microglia during PD pathophysiology that were partially rescued by L-Dopa treatment. Albeit, this L-Dopa treatment conferred phagolysosomal insufficiency on microglia in the dyskinetic Parkinsonian monkeys.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipWe thank Julie-Christine Lévesque at the Bioimaging platform of the Infectious Disease Research Centre, funded by the Canadian Foundation Innovation (CFI). We are also grateful to Laurent Grégoire, Marie-Josée Wallman, Micaël Carrier, and Nathalie Vernoux for their contribution to the study, as well as Laura Civiero for revising the manuscript. C.L. was recipient of a master training award from Fonds de Recherche du Québec – Santé (FRQS), an excellence award from Département de médecine moléculaire of Université Laval, and an excellence award Didier-Mouginot from Fondation du CHU de Québec. M.K.S.P. is supported by a scholarship from Université Laval and an excellence award from Fondation du CHU de Québec, as well as master and doctoral training awards from Canadian Institutes of Health Research (CIHR) and FRQS. M. Bordeleau is recipient a doctoral training award from FRQS. K.P. is supported by an excellence award from Fondation du CHU de Québec, as well as from Centre thématique de recherche en neurosciences and from Fondation Famille-Choquette. IOA is supported by an International Brain Research Organization African Regional Committee (IBRO-ARC) 2019 Fellowship at Université Laval, Québec, QC, Canada. F.G.I. is supported by a scholarship from the Mexican Council of Science and Technology (CONACYT). The study was funded by an operating grant from CIHR (#341846) awarded to T.D.P., L.C., M.P. and M.E.T. M.E.T. held a Tier II Canada Research Chair in Neuroimmune plasticity in health and therapy (2017-20) and now holds a Tier II Canada Research Chair in Neurobiology of Aging and Cognition (2020-25).en_US
dc.identifier.citationLecours, C., St-Pierre, M, Picard, K., Bordeleau, M., Bourque, M., Awogbindin, I. O., … Tremblay, M. (2020). Levodopa partially rescues microglial numerical, morphological, and phagolysosomal alterations in a monkey model of Parkinson’s disease. Brain, Behavior, and Immunity, 90, 81-96. https://doi.org/10.1016/j.bbi.2020.07.044.en_US
dc.identifier.urihttps://doi.org/10.1016/j.bbi.2020.07.044
dc.identifier.urihttp://hdl.handle.net/1828/12217
dc.language.isoenen_US
dc.publisherBrain, Behavior, and Immunityen_US
dc.subjectNeuroinflammation
dc.subjectMicroglia
dc.subjectBasal ganglia
dc.subjectParkinson's disease
dc.subjectMPTP monkey model
dc.subject.departmentDivision of Medical Sciences
dc.subject.departmentSchool of Medical Sciences
dc.titleLevodopa partially rescues microglial numerical, morphological, and phagolysosomal alterations in a monkey model of Parkinson's diseaseen_US
dc.typeArticleen_US

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