Mutations in the mammalian target of rapamycin pathway regulators <i>NPRL2</i> and <i>NPRL3</i> cause focal epilepsy

Ricos, Michael G.; Hodgson, Bree; Pippucci, Tommaso; Saidin, Akzam; Ong, Yeh Sze; Heron, Sarah E.; Licchetta, Laura; Bisulli, Francesca; Bayly, Marta A.; Hughes, James; Baldassari, Sara; Palombo, Flavia; Santucci, Margherita; Meletti, Stefano; Berkovic, Samuel F.; Rubboli, Guido; Thomas, Paul Q.; Scheffer, Ingrid E.; Tinuper, Paolo; Geoghegan, Joel; Schreiber, Andreas W.; Dibbens, Leanne M.

doi:10.1002/ana.24547

Cited by 195 publications

(195 citation statements)

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“…Author manuscript; available in PMC 2018 March 09. mTORC1 signaling may also be involved in epilepsy and autism more generally. Indeed, mTORC1 hyperactivation in mice through neural loss of Tsc1 or Tsc2 leads to severe epileptic seizures that are prevented by rapamycin treatment (Zeng et al, 2008), and mutations in components of the GATOR1 and KICSTOR complexes have been linked to epilepsy in humans (Basel-Vanagaite et al, 2013;Ricos et al, 2016).…”

Section: Brain Functionmentioning

confidence: 99%

mTOR Signaling in Growth, Metabolism, and Disease

Saxton

Sabatini

2017

Cell

2,165

2,497

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The mechanistic Target of Rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR-signaling network contributes to human disease, and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

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Section: Brain Functionmentioning

confidence: 99%

mTOR Signaling in Growth, Metabolism, and Disease

Saxton

Sabatini

2017

Cell

2,165

2,497

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“…DEPDC5 mutations have been identified in nocturnal frontal lobe epilepsy, familial focal epilepsy with variable foci, FCD, hemimegalencephaly, and non-lesional neocortical epilepsy, although an explanation for the wide phenotypic diversity of DEPDC5 mutations is lacking. Mutations in NPRL2, another GATOR1 subunit, are associated with focal epilepsy 74 . Surgically resected FCD from patients with known DEPDC5 or NPRL3 mutations exhibit enlarged, phospho-S6-labelled neurons and altered laminar structure, which is consistent with the finding 72,73 that these proteins, as part of the GATOR1 complex, negatively modulate mTOR.…”

Section: Gtpase-activating Proteins Toward Rags 1 (Gator1)mentioning

confidence: 99%

The mTOR signalling cascade: paving new roads to cure neurological disease

2016

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Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.

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“…DEPDC5 mutations have also been identified in cases with a wide range of clinical features associated with focal epileptic disorders, including nocturnal frontal lobe epilepsy (NFLE), temporal lobe epilepsy, (TLE) as well as familial focal epilepsy with variable foci (FFEVF). 2 2, 3, 4, 5, 6 Furthermore, DEPDC5 mutations have also been described more recently in patients with epileptic features associated with focal cortical dysplasia 6, 7, 8. A large number of mutations spanning the coding sequence of DEPDC5 have been identified in epilepsy‐related disorders with the majority (approximately 80%) of these mutations causing premature codon termination 9.…”

Section: Introductionmentioning

confidence: 99%

“…It was recently characterized as an essential member of the GATOR1 (Gap Activity Toward Rags) molecular complex acting as a key negative regulator of the mTORC1 10, 11, 12, 13. Two other components of the GATOR1 complex, NPRL2 and 3 have been shown to be mutated in familial focal epilepsy with or without focal cortical dysplasia,5, 13, 14, 15 suggesting hyperactivation of mTORC1 as a major cause of epileptic syndromes. Rodent models of Depdc5 confirm the essential role played by this mTOR regulator in development 12, 16.…”

Section: Introductionmentioning

confidence: 99%

Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

Calbiac

Dabacan²,

Marsan

et al. 2018

Ann Clin Transl Neurol

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Objective DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling.MethodsZebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy‐related disorders. In this study, we defined the expression of depdc5 during development and established an epilepsy model with reduced Depdc5 expression.ResultsHere we report a zebrafish model of Depdc5 loss‐of‐function that displays a measurable behavioral phenotype, including hyperkinesia, circular swimming, and increased neuronal activity. These phenotypic features persisted throughout embryonic development and were significantly reduced upon treatment with the mTORC1 inhibitor, rapamycin, as well as overexpression of human WT DEPDC5 transcript. No phenotypic rescue was obtained upon expression of epilepsy‐associated DEPDC5 mutations (p.Arg487* and p.Arg485Gln), indicating that these mutations cause a loss of function of the protein.InterpretationThis study demonstrates that Depdc5 knockdown leads to early‐onset phenotypic features related to motor and neuronal hyperactivity. Restoration of phenotypic features by WT but not epilepsy‐associated Depdc5 mutants, as well as by mTORC1 inhibition confirm the role of Depdc5 in the mTORC1‐dependent molecular cascades, defining this pathway as a potential therapeutic target for DEPDC5‐inherited forms of focal epilepsy.

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Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy

Cited by 195 publications

References 50 publications

mTOR Signaling in Growth, Metabolism, and Disease

mTOR Signaling in Growth, Metabolism, and Disease

The mTOR signalling cascade: paving new roads to cure neurological disease

Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

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