title: Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis.
abstract: Certain mutations within the mammalian target of rapamycin (mTOR) pathway, most notably those affecting the tuberous sclerosis complex (TSC), lead to aberrant activation of mTOR and result in a high incidence of epilepsy in humans and animal models. Although hyperactivation of mTOR has been strongly linked to the development of epilepsy and, conversely, inhibition of mTOR by rapamycin treatment is protective against seizures in several models, the downstream epileptic mechanisms have remained elusive. Autophagy, a catabolic process that plays a vital role in cellular homeostasis by mediating the turnover of cytoplasmic constituents, is negatively regulated by mTOR. Here we demonstrate that autophagy is suppressed in brain tissues of forebrain-specific conditional TSC1 and phosphatase and tensin homlog knock-out mice, both of which display aberrant mTOR activation and seizures. In addition, we also discovered that autophagy is suppressed in the brains of human TSC patients. Moreover, conditional deletion of Atg7, an essential regulator of autophagy, in mouse forebrain neurons is sufficient to promote development of spontaneous seizures. Thus, our study suggests that impaired autophagy contributes to epileptogenesis, which may be of interest as a potential therapeutic target for epilepsy treatment and/or prevention.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12208, USA.
authors.forename: John
authors.initials: J
authors.lastname: McMahon
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Huang
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Xinjun
authors.initials: X
authors.lastname: Zhu
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000071193:Autophagy-Related Protein 7