Depdc5 knockout rat: A novel model of mTORopathy

Marsan, Elise; Ishida, Saeko; Schramm, Adrien E.; Weckhuysen, Sarah; Muraca, Giuseppe; Lecas, Sarah; Liang, Ning; Treins, Caroline; Pende, Mario; Roussel, Delphine; Quyen, Michel Le Van; Mashimo, Tomoji; Kaneko, Takehito; Yamamoto, Takashi; Sakuma, Tetsushi; Mahon, Séverine; Miles, Richard; LeGuern, Eric; Charpier, Stéphane; Baulac, Stéphanie

doi:10.1016/j.nbd.2016.02.010

Cited by 77 publications

(86 citation statements)

References 50 publications

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“…DEPDC5 has been described as an essential part of the GATOR1 complex, an inhibitor of mTORC1 10, 12. In accordance with this, treatment of depdc5 knockdown fish with the mTORC1 inhibitor, rapamycin, significantly improved the deviation angle of the swimming trajectory at 72 hpf (54.9 ± 5.99 o , n = 16, for depdc5 knockdown; vs. 28.5 ± 2.75 o , n = 12, for Depdc5 knockdown + Rapamycin 0.5 μ mol/L; P = 0.002) when the drug was administered starting at the 28 hpf stage.…”

Section: Resultsmentioning

confidence: 99%

“…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. DEPDC5 homozygous null mutations cause embryonic lethality at midgestation due to a range of abnormalities such as general hypoplasia, cranial dysplasia and cardiovascular defects.…”

Section: Introductionmentioning

confidence: 85%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…In both mouse and rat models, Depdc5 loss‐of‐function was associated with increased mTOR activity. Constitutive DEPDC5 heterozygous null animals were viable and presented subtle alterations of electrographic activity12; however, they lacked overt behavioral phenotypes and seizures,12, 16 highlighting the complexity of the Depdc5 loss‐of‐function phenotype.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

Calbiac

Dabacan²,

Marsan

et al. 2018

Ann Clin Transl Neurol

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View full text Add to dashboard Cite

show abstract

“…The majority of DEPDC5 mutations discovered so far generate premature termination codons, suggesting that haploinsufficiency could be the main mechanism underlying the pathogenesis of this epileptic syndrome with or without developmental brain cortical malformations 11. Very recently, a Depdc5 knockout rat model was created to test the loss‐of‐function hypothesis 16. Lack of one copy of Depdc5 in the rat results in several neuropathological abnormalities, including neuronal migration defects and alteration of electrophysiological properties, resembling the rodent models of mTORopathies, as well as sporadic human focal epilepsies and focal cortical dysplasia (FCD) type II 16…”

Section: Discussionmentioning

confidence: 99%

Partial deletion of DEPDC5 in a child with focal epilepsy

et al. 2016

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SummaryWe report on a child, aged 47/12 years, with borderline intelligence quotient, normal brain magnetic resonance imaging, and focal epilepsy. The polysomnographic electroencephalogram recording revealed asynchronous central spikes at both brain hemispheres resembling the features observed in focal idiopathic epileptic syndromes. Array comparative genomic hybridization analysis revealed a 32‐kb partial deletion of the DEP domain‐containing protein 5 (DEPDC5) gene, involved in a wide spectrum of inherited focal epileptic syndromes. The parental origin of the deletion could not be fully ascertained because the pregnancy had been achieved through anonymous egg donation and insemination by intracytoplasmic sperm injection. However, we demonstrate that the deletion, shared by all alternatively spliced isoforms of DEPDC5, produces a transcript presumably generating a DEPDC5 protein missing the entire DEP domain. Our findings suggest that partial deletion of DEPDC5 may be sufficient to cause the focal epilepsy in our patient, highlighting the importance of the DEP domain in DEPDC5 function. This study expands the phenotypic spectrum of DEPDC5 to sporadic forms of focal idiopathic epilepsy and underscores the fact that partial deletions, albeit probably very rare, are part of the genetic spectrum of DEPDC5 mutations.

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Cardiac Investigations in Sudden Unexpected Death in DEPDC5‐Related Epilepsy

Bacq¹,

Roussel²,

Bonduelle³

et al. 2021

Annals of Neurology

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Objective: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP. Methods: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5 c/À ), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures. Results: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic-ECG records on Depdc5 c/À mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia. Interpretation: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies.

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Depdc5 knockout rat: A novel model of mTORopathy

Cited by 77 publications

References 50 publications

Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

Partial deletion of DEPDC5 in a child with focal epilepsy

Cardiac Investigations in Sudden Unexpected Death in DEPDC5‐Related Epilepsy

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