RESUMO
Huntington's disease (HD) is caused by a polyglutamine tract expansion in huntingtin (HTT). Despite HTTs ubiquitous expression, there is early and robust vulnerability in striatum, the cause of which is poorly understood. Here, we provide evidence that impaired striatal mTORC1 activity underlies varied metabolic and degenerative phenotypes in HD brain and show that introducing the constitutively active form of the mTORC1 regulator, Rheb, into HD mouse brain, alleviates mitochondrial dysfunction, aberrant cholesterol homeostasis, striatal atrophy, impaired dopamine signaling, and increases autophagy. We also find that the expression of Rhes, a striatum-enriched mTOR activator, is reduced in HD patient and mouse brain and that exogenous addition of Rhes alleviates motor deficits and improves brain pathology in HD mice. Our combined work indicates that impaired Rhes/mTORC1 activity in HD brain may underlie the notable striatal susceptibility and thus presents a promising therapeutic target for HD therapy.
Assuntos
Proteínas de Ligação ao GTP/metabolismo , Doença de Huntington/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Complexos Multiproteicos/metabolismo , Neostriado/metabolismo , Neuropeptídeos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Atrofia , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/genética , Humanos , Doença de Huntington/genética , Lipogênese/genética , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/genética , Neostriado/patologia , Fenótipo , Proteína Enriquecida em Homólogo de Ras do Encéfalo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Serina-Treonina Quinases TOR/genéticaRESUMO
In Huntington's disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had increased anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as a therapy for HD.