Show simple item record

dc.contributor.authorPinho, Brígida R
dc.contributor.authorDuarte, Ana I
dc.contributor.authorCanas, Paula M
dc.contributor.authorMoreira, Paula I
dc.contributor.authorMurphy, Michael P
dc.contributor.authorOliveira, Jorge MA
dc.date.accessioned2019-12-17T14:31:08Z
dc.date.available2019-12-17T14:31:08Z
dc.date.issued2020-01
dc.identifier.issn0891-5849
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/300029
dc.description.abstractAbnormal protein homeostasis (proteostasis), dysfunctional mitochondria, and aberrant redox signalling are often associated in neurodegenerative disorders, such as Huntington's (HD), Alzheimer's and Parkinson's diseases. It remains incompletely understood, however, how changes in redox signalling affect proteostasis mechanisms, including protein degradation pathways and unfolded protein responses (UPR). Here we address this open question by investigating the interplay between redox signalling and proteostasis in a mouse model of HD, and by examining the in vivo effects of the mitochondria-targeted antioxidant MitoQ. We performed behavioural tests in wild-type and R6/2 HD mice, examined markers of oxidative stress, UPR activation, and the status of key protein degradation pathways in brain and peripheral tissues. We show that R6/2 mice present widespread markers of oxidative stress, with tissue-specific changes in proteostasis that were more pronounced in the brain and muscle than in the liver. R6/2 mice presented increased levels of cytosolic and mitochondrial chaperones, particularly in muscle, indicating UPR activation. Treatment with MitoQ significantly ameliorated fine motor control of R6/2 mice, and reduced markers of oxidative damage in muscle. Additionally, MitoQ attenuated overactive autophagy induction in the R6/2 muscle, which has been associated with muscle wasting. Treatment with MitoQ did not alter autophagy markers in the brain, in agreement with its low brain bioavailability, which limits the risk of impairing neuronal protein clearance mechanisms. This study supports the hypotheses that abnormal redox signalling in muscle contributes to altered proteostasis and motor impairment in HD, and that redox interventions can improve muscle performance, highlighting the importance of peripheral therapeutics in HD.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.subjectMitochondria
dc.subjectAnimals
dc.subjectMice, Transgenic
dc.subjectMice
dc.subjectHuntington Disease
dc.subjectDisease Models, Animal
dc.subjectAntioxidants
dc.subjectOxidation-Reduction
dc.subjectProteostasis
dc.titleThe interplay between redox signalling and proteostasis in neurodegeneration: In vivo effects of a mitochondria-targeted antioxidant in Huntington's disease mice.
dc.typeArticle
prism.endingPage382
prism.publicationDate2020
prism.publicationNameFree Radic Biol Med
prism.startingPage372
prism.volume146
dc.identifier.doi10.17863/CAM.47101
dcterms.dateAccepted2019-11-16
rioxxterms.versionofrecord10.1016/j.freeradbiomed.2019.11.021
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-01
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.identifier.eissn1873-4596
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_U105663142)
pubs.funder-project-idMedical Research Council (MC_UU_00015/3)
pubs.funder-project-idWellcome Trust (110159/Z/15/Z)
cam.issuedOnline2019-11-18
cam.orpheus.successThu Jan 30 10:33:36 GMT 2020 - Embargo updated
rioxxterms.freetoread.startdate2021-01-31


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record