Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations

Zhang, Longbo; Huang, Tianxiang; Teaw, Shannon; Nguyen, Lena H.; Hsieh, Lawrence S.; Gong, Xuan; Burns, Lindsay H.; Bordey, Angélique

doi:10.1126/scitranslmed.aay0289

Cited by 34 publications

(31 citation statements)

References 30 publications

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“…Moreover, postnatal rapamycin treatment reduced soma size regardless of whether treatment began in neonatal or adult ages, suggesting mTORC1 hyperactivation impact neuron size via a dynamic, modifiable process. Dendrite morphology was assessed in the IUE studies targeting Pi3k, Pten, Rheb, and Depdc5, and all revealed dendritic overgrowth involving (for some) increased dendrite thickness and complexity (Chen et al, 2015;Hsieh et al, 2016;Lin et al, 2016;Ribierre et al, 2018;Sokolov et al, 2018;Zhang et al, 2019Zhang et al, , 2020Dawson et al, 2020;Onori et al, 2020;Zhong et al, 2021). Rescue of dendrite morphology by postnatal rapamycin treatment was reported in the Pi3k E545 and Rheb S16H variants, and rapamycin likely has the same effect for the other variants (Zhang et al, 2019;Zhong et al, 2021).…”

Section: Conserved Mtorc1-dependent Phenotypes Across Pi3k-mtor and Gator1 Gene Variantsmentioning

confidence: 99%

Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies

Nguyen

Bordey

2021

Front. Neuroanat.

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Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to mutations in genes along the PI3K-mTOR pathway and the GATOR1 complex causes a spectrum of neurodevelopmental disorders (termed mTORopathies) associated with malformation of cortical development and intractable epilepsy. Despite these gene variants’ converging impact on mTORC1 activity, emerging findings suggest that these variants contribute to epilepsy through both mTORC1-dependent and -independent mechanisms. Here, we review the literature on in utero electroporation-based animal models of mTORopathies, which recapitulate the brain mosaic pattern of mTORC1 hyperactivity, and compare the effects of distinct PI3K-mTOR pathway and GATOR1 complex gene variants on cortical development and epilepsy. We report the outcomes on cortical pyramidal neuronal placement, morphology, and electrophysiological phenotypes, and discuss some of the converging and diverging mechanisms responsible for these alterations and their contribution to epileptogenesis. We also discuss potential therapeutic strategies for epilepsy, beyond mTORC1 inhibition with rapamycin or everolimus, that could offer personalized medicine based on the gene variant.

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Section: Conserved Mtorc1-dependent Phenotypes Across Pi3k-mtor and Gator1 Gene Variantsmentioning

confidence: 99%

Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies

Nguyen

Bordey

2021

Front. Neuroanat.

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“…We used anti-Ki67 (clone MM1, RTU Leica Microsystem) and rabbit anti PS6 (1:100, clone 4857, Cell Signaling Technology, Danvers). Finally, we also used rabbit anti FLNA (1:250 clone EP2405Y; Abcam ab76289), as a recent study reported that filamin A antibodies stained Giant/Balloon cells and dysmorphic neurons in samples from TSC and FCD patients (Zhang et al, 2020). Primary antibody binding to tissue sections was visualized using BOND Polymer Refine Detection (Leica Microsystem) except for parvalbumin (1:100 secondary horseradish peroxidase-conjugated IgG antisheep, Abcam).…”

Section: Methodsmentioning

confidence: 99%

Progression of Fetal Brain Lesions in Tuberous Sclerosis Complex

Gelot

Represa

2020

Front. Neurosci.

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Tuberous sclerosis (TSC) is a multisystem autosomal dominant genetic disorder due to loss of function of TSC1/TSC2 resulting in increased mTOR (mammalian target of rapamycin) signaling. In the brain, TSC is characterized by the formation of specific lesions that include subependymal and white matter nodules and cortical tubers. Cells that constitute TSC lesions are mainly Giant cells and dysmorphic neurons and astrocytes, but normal cells also populate the tubers. Although considered as a developmental disorder, the histopathological features of brain lesions have been described in only a limited number of fetal cases, providing little information on how these lesions develop. In this report we characterized the development of TSC lesions in 14 fetal brains ranging from 19 gestational weeks (GW) to term and 2 postnatal cases. The study focused on the telencephalon at the level of the caudothalamic notch. Our data indicate that subcortical lesions, forming within and at the vicinity of germinative zones, are the first alterations (already detected in 19GW brains), characterized by the presence of numerous dysmorphic astrocytes and Giant, balloon-like, cells. Our data show that cortical tuber formation is a long process that initiates with the presence of dysmorphic astrocytes (by 19-21GW), progress with the apparition of Giant cells (by 24GW) and mature with the appearance of dysmorphic neurons by the end of gestation (by 36GW). Furthermore, the typical tuberal aspect of cortical lesions is only reached when bundles of neurofilament positive extensions delineate the bottom of the cortical lesion (by 36GW). In addition, our study reveals the presence of Giant cells and dysmorphic neurons immunopositive for interneuron markers such as calbindin and parvalbumin, suggesting that TSC lesions would be mosaic lesions generated from different classes of progenitors.

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“…Clinical observation, genetic analysis, and laboratory research have assisted in developing a robust understanding of the neuropathology of TSC. There remain questions as to the extent that hamartin and tuberin regulate mTORC1-independent pathways that contribute to TSC pathology (Zhang et al, 2014 , 2020 ). However, the importance of the mTOR pathway is underscored by the clinical utility of rapamycin-like compounds that inhibit mTORC1 (Franz and Capal, 2017 ).…”

Section: The Molecular Genetics Of Tscmentioning

confidence: 99%

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

Feliciano

2020

Front. Neuroanat.

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Tuberous sclerosis complex (TSC) is a model disorder for understanding brain development because the genes that cause TSC are known, many downstream molecular pathways have been identified, and the resulting perturbations of cellular events are established. TSC, therefore, provides an intellectual framework to understand the molecular and biochemical pathways that orchestrate normal brain development. The TSC1 and TSC2 genes encode Hamartin and Tuberin which form a GTPase activating protein (GAP) complex. Inactivating mutations in TSC genes (TSC1/TSC2) cause sustained Ras homologue enriched in brain (RHEB) activation of the mammalian isoform of the target of rapamycin complex 1 (mTORC1). TOR is a protein kinase that regulates cell size in many organisms throughout nature. mTORC1 inhibits catabolic processes including autophagy and activates anabolic processes including mRNA translation. mTORC1 regulation is achieved through two main upstream mechanisms. The first mechanism is regulation by growth factor signaling. The second mechanism is regulation by amino acids. Gene mutations that cause too much or too little mTORC1 activity lead to a spectrum of neuroanatomical changes ranging from altered brain size (micro and macrocephaly) to cortical malformations to Type I neoplasias. Because somatic mutations often underlie these changes, the timing, and location of mutation results in focal brain malformations. These mutations, therefore, provide gainof-function and loss-of-function changes that are a powerful tool to assess the events that have gone awry during development and to determine their functional physiological consequences. Knowledge about the TSC-mTORC1 pathway has allowed scientists to predict which upstream and downstream mutations should cause commensurate neuroanatomical changes. Indeed, many of these predictions have now been clinically validated. A description of clinical imaging and histochemical findings is provided in relation to laboratory models of TSC that will allow the reader to appreciate how human pathology can provide an understanding of the fundamental mechanisms of development.

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Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations

Cited by 34 publications

References 30 publications

Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies

Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies

Progression of Fetal Brain Lesions in Tuberous Sclerosis Complex

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

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