title: DEPDC5 as a potential therapeutic target for epilepsy.
abstract: Dishevelled, Egl-10 and Pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a protein subunit of the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 is a recently identified modulator of mechanistic target of rapamycin (mTOR) activity. mTOR is a key regulator of cell proliferation and metabolism; disruption of the mTOR pathway is implicated in focal epilepsy, both acquired and genetic. Tuberous sclerosis is the prototypic mTOR genetic syndrome with epilepsy, however GATOR1 gene mutations have recently been shown to cause lesional and non-lesional focal epilepsy. Areas covered: This review summarizes the mTOR pathway, including regulators and downstream effectors, emphasizing recent developments in the understanding of the complex role of the GATOR1 complex. We review the epilepsy types associated with mTOR overactivity, including tuberous sclerosis, polyhydramnios megalencephaly symptomatic epilepsy, cortical dysplasia, non-lesional focal epilepsy and post-traumatic epilepsy. Currently available mTOR inhibitors are discussed, primarily rapamycin analogs and ATP competitive mTOR inhibitors. Expert opinion: DEPDC5 is an attractive therapeutic target in focal epilepsy, as effects of DEPDC5 agonists would likely be anti-epileptogenic and more selective than currently available mTOR inhibitors. Therapeutic effects might be synergistic with certain existing dietary therapies, including the ketogenic diet.
authors.affiliation: a Epilepsy Research Centre, Department of Medicine , The University of Melbourne, Austin Health , Heidelberg , Victoria , Australia.|b Department of Paediatrics , Royal Children's Hospital, The University of Melbourne , Flemington , Victoria , Australia.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Myers
authors.affiliation: a Epilepsy Research Centre, Department of Medicine , The University of Melbourne, Austin Health , Heidelberg , Victoria , Australia.|b Department of Paediatrics , Royal Children's Hospital, The University of Melbourne , Flemington , Victoria , Australia.|c The Florey Institute of Neuroscience and Mental Health , Heidelberg , Victoria , Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015195:Drug Design; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D020690:GTPase-Activating Proteins / Q000235:genetics; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D012097:Repressor Proteins / Q000819:agonists* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; C000590398:DEPDC5 protein, human; D020690:GTPase-Activating Proteins; D012097:Repressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: DEPDC5; GATOR1; NPRL2; NPRL3; cortical dysplasia; focal epilepsy; mechanistic target of rapamycin; rapamycin; tuberous sclerosis