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Elucidating the molecular pathology of DEPDC5 mutation induced mTOR-hyperactivation associated with epilepsy and autism spectrum disorder

ABSTRACT: Elucidating the molecular pathology of DEPDC5 mutation induced mTOR-hyperactivation associated with epilepsy and autism spectrum disorder

PROVIDER: PRJNA1003403 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25569000.fastq.gz	Fastqsanger.gz
	SRR25569001.fastq.gz	Fastqsanger.gz
	SRR25569002.fastq.gz	Fastqsanger.gz
	SRR25569003.fastq.gz	Fastqsanger.gz
	SRR25569004.fastq.gz	Fastqsanger.gz

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Elucidating the molecular pathology of DEPDC5 mutation induced mTOR-hyperactivation associated with epilepsy and autism spectrum disorder

Project description:To observe the effects of DEPDC5-KO on the transcriptome, 3‟-mRNA analysis was performed

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Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development

Project description:Abstract Spatiotemporal regulation of the mechanistic target of rapamycin (mTOR) pathway is pivotal for establishment of brain architecture. Dysregulation of mTOR signaling is associated with a variety of neurodevelopmental disorders (NDDs). Here, we discover that the UBE4B-KLHL22 E3 ubiquitin ligase cascade regulates mTOR activity in neurodevelopment. In a mouse model with UBE4B conditionally deleted in the nervous system, animals display severe growth defects, spontaneous seizures, and premature death. Loss of UBE4B in the brains of mutant mice results in depletion of neural precursor cells (NPCs), impairment of neurogenesis, and enlargement of neuronal soma. Mechanistically, UBE4B polyubiquitinates and degrades KLHL22, an E3 ligase previously shown to degrade the GATOR1 component DEPDC5. Deletion of UBE4B causes upregulation of KLHL22 and hyperactivation of mTOR, leading to defective proliferation and differentiation of NPCs. Suppression of KLHL22 expression reverses the elevated activity of mTOR caused by acute local deletion of UBE4B in the dentate gyrus (DG). Prenatal treatment with the mTOR inhibitor rapamycin rescues neurogenesis defects in Ube4b mutant mice. Taken together, these findings demonstrate that UBE4B and KLHL22 are essential for maintenance and differentiation of the precursor pool through fine-tuning of mTOR activity.

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Epilepsy in a melanocyte-lineage mTOR hyperactivation mouse model: A novel epilepsy model.

Project description:ObjectiveTo clarify the complex mechanism underlying epileptogeneis, a novel animal model was generated.MethodsIn our previous research, we have generated a melanocyte-lineage mTOR hyperactivation mouse model (Mitf-M-Cre Tsc2 KO mice; cKO mice) to investigate mTOR pathway in melanogenesis regulation, markedly reduced skin pigmentation was observed. Very unexpectedly, spontaneous recurrent epilepsy was also developed in this mouse model.ResultsCompared with control littermates, no change was found in either brain size or brain mass in cKO mice. Hematoxylin staining revealed no obvious aberrant histologic features in the whole brains of cKO mice. Histoimmunofluorescence staining and electron microscopy examination revealed markedly increased mTOR signaling and hyperproliferation of mitochondria in cKO mice, especially in the hippocampus. Furthermore, rapamycin treatment reversed these abnormalities.ConclusionsThis study suggests that our melanocyte-lineage mTOR hyperactivation mouse is a novel animal model of epilepsy, which may promote the progress of both epilepsy and neurophysiology research.

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Project description:Biallelic pathogenic variants in STRADA, an upstream regulator of the mechanistic target of rapamycin (mTOR) pathway, result in megalencephaly, drug-resistant epilepsy, and severe intellectual disability. This study seeks to understand how mTOR pathway hyperactivity alters cell fate specification in dorsal and ventral forebrain development using STRADA knock-out human stem cell derived brain organoids. In both dorsal and ventral forebrain STRADA knock-out organoids, neurogenesis is delayed, with a predilection for stem cell maintenance and an increase in outer radial glia. Ventrally, interneuron subtypes shift to an increase in neuropeptide-Y expressing cells. Inhibition of the mTOR pathway with rapamycin results in rescue for most phenotypes. When mTOR pathway variants are present in all cells of the developing brain, overproduction of interneurons and altered interneuron cell fate may underlie mechanisms of megalencephaly, epilepsy, and cognitive impairment. Our findings suggest mTOR inhibition during fetal brain development as a potential therapeutic strategy in STRADA deficiency.

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Project description:Autism is present in 1% of the population, yet treatments are extremely limited. We identified homozygous inactivating mutations in the BCKDK gene in families presenting with autism and epilepsy. The encoded branched chain ketoacid dehydrogenase kinase protein is responsible for phosphorylation-mediated inactivation of the E1-alpha subunit of branched chain ketoacid dehydrogenase, itself mutated in Maple Syrup Urine Disease (MSUD). Patients with homozygous BCKDK mutations display reductions in BCKDK mRNA and protein, E1-alpha phosphorylation and serum branched chain amino acids (BCAAs). Bckdk knockout mice show abnormal brain amino acids profiles and neurobehavioral defects, which are largely corrected by dietary BCAA supplementation. Thus autism presenting with epilepsy due to BCKDK mutations represent a new and potentially treatable disease.

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