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Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia

2019-11Journal article Restricted
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dc.contributor.authorNóbrega, Clévio
dc.contributor.authorMendonca, Liliana
dc.contributor.authorMarcelo, Adriana
dc.contributor.authorLamaziere, Antonin
dc.contributor.authorTome, Sandra
dc.contributor.authorDespres, Gaetan
dc.contributor.authorMatos, Carlos A
dc.contributor.authorMechmet, Fatich
dc.contributor.authorLangui, Dominique
dc.contributor.authorden Dunnen, Wilfred
dc.contributor.authorde Almeida, Luis Pereira
dc.contributor.authorCartier, Nathalie
dc.contributor.authorAlves, Sandro
dc.date.accessioned2020-07-24T10:51:06Z
dc.date.available2020-07-24T10:51:06Z
dc.date.issued2019-11
dc.description.abstractSpinocerebellar ataxias (SCAs) are devastating neurodegenerative disorders for which no curative or preventive therapies are available. Deregulation of brain cholesterol metabolism and impaired brain cholesterol turnover have been associated with several neurodegenerative diseases. SCA3 or Machado-Joseph disease (MJD) is the most prevalent ataxia worldwide. We show that cholesterol 24-hydroxylase (CYP46A1), the key enzyme allowing efflux of brain cholesterol and activating brain cholesterol turnover, is decreased in cerebellar extracts from SCA3 patients and SCA3 mice. We investigated whether reinstating CYP46A1 expression would improve the disease phenotype of SCA3 mouse models. We show that administration of adeno-associated viral vectors encoding CYP46A1 to a lentiviral-based SCA3 mouse model reduces mutant ataxin-3 accumulation, which is a hallmark of SCA3, and preserves neuronal markers. In a transgenic SCA3 model with a severe motor phenotype we confirm that cerebellar delivery of AAVrh10-CYP46A1 is strongly neuroprotective in adult mice with established pathology. CYP46A1 significantly decreases ataxin-3 protein aggregation, alleviates motor impairments and improves SCA3-associated neuropathology. In particular, improvement in Purkinje cell number and reduction of cerebellar atrophy are observed in AAVrh10-CYP46A1-treated mice. Conversely, we show that knocking-down CYP46A1 in normal mouse brain impairs cholesterol metabolism, induces motor deficits and produces strong neurodegeneration with impairment of the endosomal-lysosomal pathway, a phenotype closely resembling that of SCA3. Remarkably, we demonstrate for the first time both in vitro, in a SCA3 cellular model, and in vivo, in mouse brain, that CYP46A1 activates autophagy, which is impaired in SCA3, leading to decreased mutant ataxin-3 deposition. More broadly, we show that the beneficial effect of CYP46A1 is also observed with mutant ataxin-2 aggregates. Altogether, our results confirm a pivotal role for CYP46A1 and brain cholesterol metabolism in neuronal function, pointing to a key contribution of the neuronal cholesterol pathway in mechanisms mediating clearance of aggregate-prone proteins. This study identifies CYP46A1 as a relevant therapeutic target not only for SCA3 but also for other SCAs.
dc.description.sponsorshipNeur ATRIS: A Translational Research Infrastructure for Biotherapies in Neurosciences
dc.description.sponsorshipFondation pour la Recherche Medicale, Bioingenierie pour la SanteFondation pour la Recherche Medicale [DBS20140930765]
dc.description.sponsorshipSATT (Societe d'Acceleration de Transfert Technologique) Ile de France Innov
dc.description.sponsorshipParis Saclay University
dc.description.sponsorshipEuropean Regional Development Fund (ERDF)European Union (EU) [CENTRO-01-0145-FEDER-000008]
dc.description.sponsorshipPortuguese national funds via FCT-Fundacao para a Ciencia e a Tecnologia, I.P. [POCI-01-0145-FEDER-016719 (PTDC/NEU-NMC/0084/2014), POCI-01-0145-FEDER-007440 (UID/NEU/04539/2013), POCI-01-0145-FEDER-016390]
dc.description.sponsorshipFCT under EU [CENTRO-01-0145-FEDER022095, JPCOFUND/0001/2015, JPCOFUND/0005/2015]
dc.description.sponsorshipEuropean UnionEuropean Union (EU) [643417]
dc.description.sponsorshipRichard Chin and Lily Lock Machado Joseph Disease Research Fund
dc.description.sponsorshipNational Ataxia Foundation
dc.description.sponsorshipFrench Muscular Dystrophy Association (AFM-Telethon)
dc.description.sponsorshipAtaxia UK
dc.description.sponsorshipCENTRO 2020
dc.description.sponsorshipFCTPortuguese Foundation for Science and Technology
dc.description.sponsorshipFCTPortuguese Foundation for Science and Technology [SFRH/BD/133192/2017]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1007/s00401-019-02019-7
dc.identifier.issn0001-6322
dc.identifier.urihttp://hdl.handle.net/10400.1/14197
dc.language.isoeng
dc.peerreviewedyes
dc.publisherSpringer
dc.relationERA-NET for establishing synergies between the Joint Programming on Neurodegenerative Diseases Research and Horizon 2020
dc.subjectMachado-Joseph disease
dc.subjectDominant cerebellar-ataxia
dc.subjectMutant ataxin-3
dc.subjectRat model
dc.subject24-hydroxylase
dc.subjectGene
dc.subjectCyp46A1
dc.subjectRepeat
dc.subjectNeurodegeneration
dc.subjectAbnormalities
dc.subjectAtaxia
dc.subjectCholesterol metabolism
dc.subject24-Cholesterol hydroxylase
dc.subjectAutophagy
dc.subjectSCA animal models
dc.subjectSCA patients
dc.titleRestoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleERA-NET for establishing synergies between the Joint Programming on Neurodegenerative Diseases Research and Horizon 2020
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/643417/EU
oaire.citation.endPage858
oaire.citation.issue5
oaire.citation.startPage837
oaire.citation.titleActa Neuropathologica
oaire.citation.volume138
oaire.fundingStreamH2020
person.familyNameNóbrega
person.familyNameMarcelo
person.familyNameAlbuquerque Andrade de Matos
person.givenNameClévio
person.givenNameAdriana
person.givenNameCarlos Adriano
person.identifier.ciencia-idC510-7F41-BAF8
person.identifier.ciencia-id7613-00C2-1621
person.identifier.ciencia-idDC14-C299-222A
person.identifier.orcid0000-0002-8312-5292
person.identifier.orcid0000-0002-7327-0170
person.identifier.orcid0000-0002-9019-7569
person.identifier.ridM-6047-2013
person.identifier.scopus-author-id24473454000
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsrestrictedAccess
rcaap.typearticle
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relation.isAuthorOfPublication3bed3cc3-e36a-445b-8d7d-4d4615ff4c4c
relation.isAuthorOfPublication31434f2c-76dd-49e4-a78e-324ab36b81bb
relation.isAuthorOfPublication.latestForDiscovery31434f2c-76dd-49e4-a78e-324ab36b81bb
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relation.isProjectOfPublication.latestForDiscoveryf83d8467-3845-465e-97d6-91c6ed1f4267

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