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

  • Clévio Nóbrega
  • Liliana Mendonça
  • Adriana Marcelo
  • Antonin Lamazière
  • Sandra Tomé
  • Gaetan Despres
  • Carlos A. Matos
  • Fatich Mechmet
  • Dominique Langui
  • Wilfred den Dunnen
  • Luis Pereira de AlmeidaEmail author
  • Nathalie CartierEmail author
  • Sandro AlvesEmail author
Original Paper


Spinocerebellar 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.


Ataxia Cholesterol metabolism 24-Cholesterol hydroxylase Autophagy SCA animal models SCA patients 



This work was supported by NeurATRIS: A Translational Research Infrastructure for Biotherapies in Neurosciences, the Fondation pour la Recherche Médicale, Bioingénierie pour la Santé 2014 “Project DBS20140930765”, Paris Biotech Santé incubator, the SATT (Société d’Accélération de Transfert Technologique) Ile de France Innov, E.rare: E-Rare Joint Transnational Call for Proposals 2017 “Transnational Research Projects for Innovative Therapeutic Approaches for Rare Diseases”, Biotheralliance network from the Paris Saclay University and Brainvectis. This work was also financed by the European Regional Development Fund (ERDF), through the CENTRO 2020 Regional Operational Programme under project CENTRO-01-0145-FEDER-000008:BrainHealth 2020, through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization and Portuguese national funds via FCT—Fundação para a Ciência e a Tecnologia, I.P., under projects POCI-01-0145-FEDER-016719 (PTDC/NEU-NMC/0084/2014), POCI-01-0145-FEDER-007440 (UID/NEU/04539/2013) and POCI-01-0145-FEDER-016390:CANCEL STEM, and through CENTRO 2020 and FCT under project CENTRO-01-0145-FEDER-022095:ViraVector; also by projects ESMI (JPCOFUND/0001/2015) and ModelPolyQ (JPCOFUND/0005/2015) under the EU Joint Program—Neurodegenerative Disease Research (JPND), the last two co-funded by the European Union H2020 program, GA No.643417 and national funds (FCT), and by the Richard Chin and Lily Lock Machado Joseph Disease Research Fund; and the National Ataxia Foundation. CN laboratory is supported by the French Muscular Dystrophy Association (AFM-Téléthon), the Ataxia UK, and the FCT. AM is supported by a Ph.D. fellowship from FCT (SFRH/BD/133192/2017).

Compliance with ethical standards

Conflict of interest

The authors declare financial interest. CN, LM, NC, LPA and SA are inventors of patent applications claiming the use of AAV-CYP46A1 therapy in spinocerebellar ataxias.

Supplementary material

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biomedical Sciences and MedicineUniversity of AlgarveFaroPortugal
  2. 2.Centre for Biomedical ResearchUniversity of AlgarveFaroPortugal
  3. 3.Algarve Biomedical CenterUniversity of AlgarveFaroPortugal
  4. 4.Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal
  5. 5.INSERM, Saint-Antoine Research Center, Sorbonne Université, Faculté de Médecine, AP-HP, Hôpital Saint Antoine, Département PM2ParisFrance
  6. 6.Institut du Cerveau et de la Moelle épinière, ICM, INSERM U1127, CNRS UMR7225, Sorbonne Université, Hôpital Pitié-SalpêtrièreParisFrance
  7. 7.Department of Pathology and Medical Biology, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
  8. 8.INSERM U1169 92265 Fontenay aux Roses and Université Paris-Sud, Université Paris SaclayOrsayFrance
  9. 9.INSERM U1127, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-SalpêtrièreParisFrance
  10. 10.Faculty of PharmacyUniversity of CoimbraCoimbraPortugal
  11. 11.Brainvectis, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-SalpêtrièreParisFrance

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