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Title: Increased levels of rictor prevent mutant huntingtin-induced neuronal degeneration
Author: Creus Muncunill, Jordi
Rué Cabré, Laura
Alcalá Vida, Rafael
Badillos Rodríguez, Raquel
Romaní Aumedes, Joan
Marco, Sonia
Alberch i Vié, Jordi
Pérez Otaño, Isabel
Malagelada Grau, Cristina
Pérez Navarro, Esther
Keywords: Proteïnes quinases
Corea de Huntington
Mort cel·lular
Protein kinases
Huntington's chorea
Cell death
Issue Date: Oct-2018
Publisher: Humana Press.
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.
Note: Versió postprint del document publicat a:
It is part of: Molecular Neurobiology, 2018, vol. 55, num. 10, p. 7728-7742
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ISSN: 0893-7648
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Neurociències (UBNeuro))
Articles publicats en revistes (Biomedicina)

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