title: GATOR1 complex: the common genetic actor in focal epilepsies.
abstract: The mammalian or mechanistic target of rapamycin (mTOR) signalling pathway has multiple roles in regulating physiology of the whole body and, particularly, the brain. Deregulation of mTOR signalling has been associated to various neurological conditions, including epilepsy. Mutations in genes encoding components of Gap Activity TOward Rags 1 (GATOR1) (DEPDC5, NPRL2 and NPRL3), a complex involved in the inhibition of the mTOR complex 1 (mTORC1), have been recently implicated in the pathogenesis of a wide spectrum of focal epilepsies (FEs), both lesional and non-lesional. The involvement of DEPDC5, NPRL2 and NRPL3 in about 10% of FEs is in contrast to the concept that specific seizure semiology points to the main involvement of a distinct brain area. The hypothesised pathogenic mechanism underlying epilepsy is the loss of the inhibitory function of GATOR1 towards mTORC1. The identification of the correct therapeutic strategy in patients with FE is challenging, especially in those with refractory epilepsy and/or malformations of cortical development (MCDs). In such cases, surgical excision of the epileptogenic zone is a curative option, although the long-term outcome is still undefined. The GATOR1/mTOR signalling represents a promising therapeutic target in FEs due to mutations in mTOR pathway genes, as in tuberous sclerosis complex, another MCD-associated epilepsy caused by mTOR signalling hyperactivation.
authors.affiliation: Department of Medical and Surgical Sciences-Medical Genetics Unit, Università degli Studi di Bologna Azienda Ospedaliera Sant'Orsola-Malpighi, Bologna, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Baldassari
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Licchetta
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tinuper
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bisulli
authors.affiliation: Department of Medical and Surgical Sciences-Medical Genetics Unit, Università degli Studi di Bologna Azienda Ospedaliera Sant'Orsola-Malpighi, Bologna, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D004828:Epilepsies, Partial / Q000235:genetics*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: DEPDC5; Focal Epilepsy; GATOR1; Malformations of Cortical Development; mTOR