Prevention of premature death and seizures in a Depdc5 mouse epilepsy model through inhibition of mTORC1

Klofas, Lindsay K.; Short, Brittany Parker; Zhou, Chengwen; Carson, Robert P.

doi:10.1093/hmg/ddaa068

Cited by 26 publications

(37 citation statements)

References 46 publications

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“… 124 In preclinical models of GATOR1-related epilepsies, Depdc5 conditional knockout mice display a propensity for terminal seizures, resembling the human phenomenon of SUDEP. 34 , 53 , 55 Mice with focal cortical biallelic Depdc5 deletions had clusters of focal onset tonic-clonic seizures, followed by EEG suppression, and in some cases death. 34 Depdc5 , Nprl2 and Nprl3 expression analyses in mouse tissues revealed a general elevation in all brain regions compared with other organs, with expression highest in brain cortex.…”

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

“…In a Depdc5 conditional knockout mouse model, rapamycin reduced seizure frequency and extended survival. 55 Treatment with sirolimus rendered an infant with NPRL3 -related DRE seizure free after three weeks of therapy. 128 Clinical studies are warranted to determine the effectiveness of mTOR inhibitors for DRE in the GATORopathies ( Fig.…”

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

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Epilepsy in the mTORopathies: opportunities for precision medicine

Moloney

Cavalleri

Delanty

2021

Brain Communications

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The mechanistic target of rapamycin (mTOR) signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mTOR cascade funnels through mTOR complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mTOR complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mTOR regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mTOR pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mTOR complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively the mTORopathies are characterised by excessive mTOR pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically-mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalised medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mTOR pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mTOR inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.

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Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

Epilepsy in the mTORopathies: opportunities for precision medicine

Moloney

Cavalleri

Delanty

2021

Brain Communications

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“…Perhaps a small molecule or cell-penetrant peptide that mimics the raptor claw could effectively prevent lysosomal recruitment of mTORC1 and thus diminish mTORC1 signaling in a therapeutically useful manner. This could have value, for example, in the treatment of inherited focal epilepsy, which is caused by mutations in DEPDC5 and tends to be drug-resistant [128] or for by-passing the paradoxical increase in cell growth sometimes observed with rapamycin and its analogs [129]. In a similar vein, small molecules that antagonize the binding of Rheb to mTORC1 could find utility in the treatment of tuberous sclerosis complex or in cancers in which the Rheb axis has been corrupted.…”

Section: Perspectivesmentioning

confidence: 99%

Structural Insights into TOR Signaling

Tafur

Kefauver

Loewith

2020

Genes

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The Target of Rapamycin (TOR) is a highly conserved serine/threonine protein kinase that performs essential roles in the control of cellular growth and metabolism. TOR acts in two distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in humans), which maintain different aspects of cellular homeostasis and orchestrate the cellular responses to diverse environmental challenges. Interest in understanding TOR signaling is further motivated by observations that link aberrant TOR signaling to a variety of diseases, ranging from epilepsy to cancer. In the last few years, driven in large part by recent advances in cryo-electron microscopy, there has been an explosion of available structures of (m)TORC1 and its regulators, as well as several (m)TORC2 structures, derived from both yeast and mammals. In this review, we highlight and summarize the main findings from these reports and discuss both the fascinating and unexpected molecular biology revealed and how this knowledge will potentially contribute to new therapeutic strategies to manipulate signaling through these clinically relevant pathways.

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“…This hypothesis was originally formulated after work in animal models conditionally expressing the β2 Val287Leu nAChR subunit [65]. Subsequently, the identification of DEPDC5 loss of function mutations led to recognize a spectrum of epilepsy syndromes, among which ADSHE, associated with human brain malformation [101,106], as is also indicated by the first murine models in which DEPD5 has been deleted [148][149][150].…”

Section: Developmental Aspects Of Adshe and Implications For Therapymentioning

confidence: 99%

“…Promising results have been obtained in a murine strain in which conditional deletion of Depdc5 in dorsal telencephalic neuroprogenitor cells leads to macrocephaly, accompanied by spontaneous seizures and premature death. Early inhibition of mTORC1 with rapamycin improves survival and prevents seizures, which further encourages the search of effective developmental windows for anti-seizure treatment [150].…”

Section: Developmental Aspects Of Adshe and Implications For Therapymentioning

confidence: 99%

Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology

et al. 2020

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Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic focal seizures, mainly arising in the neocortex during non-rapid eye movements (NREM) sleep. The familial form is autosomal dominant SHE (ADSHE), which can be caused by mutations in genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR), Na+-gated K+ channels, as well as non-channel signaling proteins, such as components of the gap activity toward rags 1 (GATOR1) macromolecular complex. The causative genes may have different roles in developing and mature brains. Under this respect, nicotinic receptors are paradigmatic, as different pathophysiological roles are exerted by distinct nAChR subunits in adult and developing brains. The widest evidence concerns α4 and β2 subunits. These participate in heteromeric nAChRs that are major modulators of excitability in mature neocortical circuits as well as regulate postnatal synaptogenesis. However, growing evidence implicates mutant α2 subunits in ADSHE, which poses interpretive difficulties as very little is known about the function of α2-containing (α2*) nAChRs in the human brain. Planning rational therapy must consider that pharmacological treatment could have different effects on synaptic maturation and adult excitability. We discuss recent attempts towards precision medicine in the mature brain and possible approaches to target developmental stages. These issues have general relevance in epilepsy treatment, as the pathogenesis of genetic epilepsies is increasingly recognized to involve developmental alterations.

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Prevention of premature death and seizures in a Depdc5 mouse epilepsy model through inhibition of mTORC1

Cited by 26 publications

References 46 publications

Epilepsy in the mTORopathies: opportunities for precision medicine

Epilepsy in the mTORopathies: opportunities for precision medicine

Structural Insights into TOR Signaling

Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology

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