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Increased Levels of Rictor Prevent Mutant Huntingtin-Induced Neuronal Degeneration

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Abstract

Rictor associates with mTOR to form the mTORC2 complex, which activity regulates neuronal function and survival. Neurodegenerative diseases are characterized by the presence of neuronal dysfunction and cell death in specific brain regions such as for example Huntington’s disease (HD), which is characterized by the loss of striatal projection neurons leading to motor dysfunction. Although HD is caused by the expression of mutant huntingtin, cell death occurs gradually suggesting that neurons have the capability to activate compensatory mechanisms to deal with neuronal dysfunction and later cell death. Here, we analyzed whether mTORC2 activity could be altered by the presence of mutant huntingtin. We observed that Rictor levels are specifically increased in the striatum of HD mouse models and in the putamen of HD patients. Rictor-mTOR interaction and the phosphorylation levels of Akt, one of the targets of the mTORC2 complex, were increased in the striatum of the R6/1 mouse model of HD suggesting increased mTORC2 signaling. Interestingly, acute downregulation of Rictor in striatal cells in vitro reduced mTORC2 activity, as shown by reduced levels of phospho-Akt, and increased mutant huntingtin-induced cell death. Accordingly, overexpression of Rictor increased mTORC2 activity counteracting cell death. Furthermore, normalization of endogenous Rictor levels in the striatum of R6/1 mouse worsened motor symptoms suggesting an induction of neuronal dysfunction. In conclusion, our results suggest that increased Rictor striatal levels could counteract neuronal dysfunction induced by mutant huntingtin.

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Acknowledgements

We are very grateful to Drs. Saavedra and Azkona (University of Barcelona) for critical reading of the manuscript, Dr. Azkona for his advice on intrastriatal injection of AAVs, Dr. Lucas (Centre for Molecular Biology “Severo Ochoa,” Madrid, Spain) for providing the plasmids expressing wild-type or mhtt fused to CFP, Dr. MacDonald (Massachusetts General Hospital, Boston, Massachusetts, USA) for the generous gift of STHdhQ7/Q7 cell line and HdhQ111/Q111 mice, Dr. Hayden (Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada) for providing the YAC 128 mice, and Dr. Bayascas for the generous gift of antibodies against phosphorylated and total PRAS40. We also thank the Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS (Barcelona, Spain) for providing human tissue samples, Ana López and Maria Teresa Muñoz for their technical support, and Dr. Maria Calvo, Anna Bosch and Elisenda Coll from the Advanced Optical Microscopy Unit from Scientific and Technological Centers from the University of Barcelona for their support and advice. This work was supported by the project PI13/01250 integrado en el Plan Nacional de I+D+I y cofinanciado por el ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER), Ministerio de Economia y Competitividad (grants SAF2010-21058; CSD2008-00005, SAF2013-48983-R; SAF2013-45888R and SAF2016-08573-R), Fundació La Marató de TV3, Catalunya (grant 20140130), European Commission with a Marie Curie International Reintegration Grant (PIRG08-GA-2010-276957), Spain, funds obtained via the crowdfunding platform Goteo.org and sponsored by “Mememtum: early detection of neurological disorders,” Portal d’Avall SL, the UTE project CIMA and a NARSAD Independent Investigator Award. R.A. is a fellow of Ministerio de Economia y Competitividad, Spain.

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Author notes

  1. Laura Rué

    Present address: Department of Neurosciences, Experimental Neurology; VIB Center for Brain & Disease Research, Laboratory of Neurobiology, KU Leuven – University of Leuven, Leuven, Belgium

  2. Jordi Creus-Muncunill and Laura Rué contributed equally to this work.

Authors and Affiliations

  1. Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, E-08036, Barcelona, Catalonia, Spain

    Jordi Creus-Muncunill, Laura Rué, Rafael Alcalá-Vida, Raquel Badillos-Rodríguez, Joan Romaní-Aumedes, Jordi Alberch, Cristina Malagelada & Esther Pérez-Navarro

  2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain

    Jordi Creus-Muncunill, Laura Rué, Rafael Alcalá-Vida, Raquel Badillos-Rodríguez, Jordi Alberch & Esther Pérez-Navarro

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    Jordi Creus-Muncunill, Laura Rué, Rafael Alcalá-Vida, Raquel Badillos-Rodríguez, Jordi Alberch & Esther Pérez-Navarro

  4. Laboratorio de Neurobiología Celular, Centro de Investigación Médica Aplicada y Universidad de Navarra, Pamplona, Spain

    Sonia Marco & Isabel Perez-Otaño

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Correspondence to Esther Pérez-Navarro.

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All procedures were performed in compliance with the NIH Guide for the Care and Use of Laboratory Animals and approved by the local animal care committee of Universitat de Barcelona following European (2010/63/UE) and Spanish (RD53/2013) regulations for the care and use of laboratory animals.

Human samples were obtained following the guidelines and approval of the local ethics committee (Hospital Clínic of Barcelona’s Clinical Research Ethics Committee).

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The authors declare that they have no competing interests.

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Creus-Muncunill, J., Rué, L., Alcalá-Vida, R. et al. Increased Levels of Rictor Prevent Mutant Huntingtin-Induced Neuronal Degeneration. Mol Neurobiol 55, 7728–7742 (2018). https://doi.org/10.1007/s12035-018-0956-5

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