title: Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function.
abstract: Angelman syndrome (AS) is a neurogenetic disorder caused by deficiency of maternally expressed ubiquitin-protein ligase E3A (UBE3A), an E3 ligase that targets specific proteins for proteasomal degradation. Although motor function impairment occurs in all patients with AS, very little research has been done to understand and treat it. The present study focuses on Ube3A deficiency-induced alterations in signaling through the mechanistic target of rapamycin (mTOR) pathway in the cerebellum of the AS mouse model and on potential therapeutic applications of rapamycin. Levels of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR, were increased in AS mice compared with wild-type mice; however, TSC2 inhibitory phosphorylation was also increased. Correspondingly, levels of phosphorylated/active mTOR were increased. Phosphorylation of the mTORC1 substrates S6 kinase 1 (S6K1) and S6 was elevated, whereas that of the mTORC2 substrates AKT and N-myc downstream regulated 1 was decreased, suggesting enhanced mTORC1 but inhibited mTORC2 signaling. Semi-chronic treatment of AS mice with rapamycin not only improved their motor performance but also normalized mTORC1 and mTORC2 signaling. Furthermore, inhibitory phosphorylation of rictor, a key regulatory/structural subunit of the mTORC2 complex, was increased in AS mice and decreased after rapamycin treatment. These results indicate that Ube3A deficiency leads to overactivation of the mTORC1-S6K1 pathway, which in turn inhibits rictor, resulting in decreased mTORC2 signaling in Purkinje neurons of AS mice. Finally, rapamycin treatment also improved dendritic spine morphology in AS mice, through inhibiting mTORC1 and possibly enhancing mTORC2-mediated regulation of synaptic cytoskeletal elements. Collectively, our results indicate that the imbalance between mTORC1 and mTORC2 activity may contribute to synaptic pathology and motor impairment in AS.
authors: Basic Medical Sciences, College of Osteopathic Medicine of the Pacific and.
authors: Jiandong
authors: J
authors: Sun
authors: Basic Medical Sciences, College of Osteopathic Medicine of the Pacific and Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California 91766.
authors: Yan
authors: Y
authors: Liu
authors: Basic Medical Sciences, College of Osteopathic Medicine of the Pacific and.
authors: Stephanie
authors: S
authors: Moreno
authors: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California 91766.
authors: Michel
authors: M
authors: Baudry
authors: Basic Medical Sciences, College of Osteopathic Medicine of the Pacific and xbi@westernu.edu.
authors: Xiaoning
authors: X
authors: Bi
mesh_terms: D017204:Angelman Syndrome / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: Angelman syndrome; Purkinje neuron; TSC2; mTOR; phosphorylation; rictor