Single-cell profiling of cortical tubers in tuberous sclerosis complex shows molecular structure preservation and massive reorganization of metabolism DOI Creative Commons
Frederik N. F. Sørensen, Tin Luka Petanjek,

Mirte Scheper

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Abstract Tuberous sclerosis complex (TSC) is a multisystemic genetic disorder associated with loss-of-function mutations in the TSC1 or TSC2 gene, which lead mTOR pathway hyperactivation and epileptogenesis. Cortical tubers are hallmark of TSC represent disorganized cortical structure underlying generation focal seizures. Here, we report single-nucleus RNA sequencing resected vs matched pediatric controls. Strikingly, spite severe disorganization, found that preserve all neuronal subtypes, even rarest ones. Moreover, showed principal neurons largely spatial position based on transcriptional signatures. Principal layer 1-2 GABAergic modulate upper circuits exhibited largest gene expression changes. Interestingly, multiple changes counteracted hyperactivation. neuronal, but not glial, networks massive metabolic reorganization reduction mitochondrial respiration concomitant switch to fatty acid metabolism. Finally, show neuron-specific AMPA receptor signaling might underlie epileptogenesis could potential candidate for therapeutic targeting.

Language: Английский

Mechanism of podophyllotoxin-induced ovarian toxicity via the AMPK/TSC1/mTOR/ULK1 axis in rats on the basis of toxicological evidence chain (TEC) concept DOI Creative Commons
Jingjing Li,

Zhang Yanzhao,

Mingyue Wei

et al.

Ecotoxicology and Environmental Safety, Journal Year: 2024, Volume and Issue: 290, P. 117617 - 117617

Published: Dec. 31, 2024

Language: Английский

Citations

3
The Development of Methods of BLOTCHIP®-MS for Peptidome: Small Samples in Tuberous Sclerosis DOI Creative Commons
Kunio Yui, George Imataka, Kotaro Yuge

et al.

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(1), P. 34 - 34

Published: Jan. 7, 2025

Mutations in TSC1 or TSC2 axons induce tuberous sclerosis complex. Neurological manifestations mainly include epilepsy and autism spectrum disorder (ASD). ASD is the presenting symptom (25-50% of patients). was observed at significantly higher frequencies participants with than those mutations. The occurrence mutations about 50% larger TSC1. Therefore, may develop due to deficiency. regulates microRNA biogenesis Microprocessor activity via GSK3β. Of reference, everolimus has best treatment target because potency interactions mTORC2 rather rapamycin. genes result constitutive hyperactivation mammalian rapamycin (mTOR) pathway, contributing growth benign tumors hamartomas various organs. were associated a more severe phenotypic inhibition mTOR cascade. There are few studies on peptide analysis this relation everolimus. Only one study reported that, ten plasma samples, pre-melanosome protein (PMEL) S-adenosylmethionine (SAM) changed as diagnostic prognostic effects. Our Protosera Inc (Osaka, Japan) revealed that three peptides related inflammation two patients sclerosis, who showed 30% decrease symptoms following treatment. PMEL SAM

Language: Английский

Citations

0
Oncogenic activation of PI3KCA in cancers: Emerging targeted therapies in precision oncology DOI Creative Commons
Yuxiang Wang, Valery Rozen, Yiqing Zhao

et al.

Genes & Diseases, Journal Year: 2024, Volume and Issue: 12(2), P. 101430 - 101430

Published: Sept. 10, 2024

Phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of a p110 catalytic subunit and p85 regulatory subunit. The

Language: Английский

Citations

1
Identification of a novel TSC1 variant in a family with developmental and epileptic encephalopathies: A case report and literature review DOI Creative Commons
Chao Wang, Jin Zhai, Yongjun Chen

et al.

Medicine, Journal Year: 2024, Volume and Issue: 103(42), P. e40151 - e40151

Published: Oct. 18, 2024

Tuberous sclerosis (TSC) is an autosomal dominant neurocutaneous syndrome resulting from mutations in the tumor suppressor genes TSC1 and TSC2. Unfortunately, absence of accurate diagnosis has significantly impacted well-being both patients their families. Furthermore, pathogenicity numerous variants remains unverified, which could potentially result misinterpretation functional implications.

Language: Английский

Citations

0
Rare nonsynonymous germline and mosaic de novo variants in Japanese patients with schizophrenia DOI Open Access
Yuichiro Watanabe, M. Nishioka,

Ryo Morikawa

et al.

Psychiatry and Clinical Neurosciences, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 22, 2024

Whole-exome sequencing (WES) studies have revealed that germline de novo variants (gDNVs) contribute to the genetic etiology of schizophrenia. However, contribution mosaic DNVs (mDNVs) risk schizophrenia remains be elucidated. In present study, we systematically investigated gDNVs and mDMVs in a Japanese population.

Language: Английский

Citations

0
Single-cell profiling of cortical tubers in tuberous sclerosis complex shows molecular structure preservation and massive reorganization of metabolism DOI Creative Commons
Frederik N. F. Sørensen, Tin Luka Petanjek,

Mirte Scheper

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Abstract Tuberous sclerosis complex (TSC) is a multisystemic genetic disorder associated with loss-of-function mutations in the TSC1 or TSC2 gene, which lead mTOR pathway hyperactivation and epileptogenesis. Cortical tubers are hallmark of TSC represent disorganized cortical structure underlying generation focal seizures. Here, we report single-nucleus RNA sequencing resected vs matched pediatric controls. Strikingly, spite severe disorganization, found that preserve all neuronal subtypes, even rarest ones. Moreover, showed principal neurons largely spatial position based on transcriptional signatures. Principal layer 1-2 GABAergic modulate upper circuits exhibited largest gene expression changes. Interestingly, multiple changes counteracted hyperactivation. neuronal, but not glial, networks massive metabolic reorganization reduction mitochondrial respiration concomitant switch to fatty acid metabolism. Finally, show neuron-specific AMPA receptor signaling might underlie epileptogenesis could potential candidate for therapeutic targeting.

Language: Английский

Citations

0