Brain malformations and seizures by impaired chaperonin function of TRiC

Science, Год журнала: 2024, Номер 386(6721), С. 516 - 525

Опубликована: Окт. 31, 2024

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants core protein-folding machinery TRiC/CCT individuals with malformations, intellectual disability, seizures. The chaperonin TRiC is an obligate hetero-oligomer, identify seven its eight subunits, all which impair function or assembly through different mechanisms. Transcriptome proteome analyses patient-derived fibroblasts demonstrate various consequences impairment. results reveal unexpected widespread role for protein folding development central nervous system define a disease spectrum "TRiCopathies."

Язык: Английский

---

The Ferret as a Model System for Neocortex Development and Evolution

Frontiers in Cell and Developmental Biology, Год журнала: 2021, Номер 9

Опубликована: Апрель 29, 2021

The neocortex is the largest part of cerebral cortex and a key structure involved in human behavior cognition. Comparison development across mammals reveals that proliferative capacity neural stem progenitor cells length neurogenic period are essential for regulating size complexity, which turn thought to be instrumental increased cognitive abilities humans. domesticated ferret, Mustela putorius furo , an important animal model neurodevelopment its complex postnatal cortical folding, long forebrain accessibility genetic manipulation vivo . Here, we discuss molecular, cellular, histological features make this small gyrencephalic carnivore suitable study physiological pathological mechanisms expanded neocortex. We particularly focus on cell proliferation, neuronal differentiation, visual system development, neurodevelopmental pathologies. further technological advances have enabled ferret Finally, compare with those other organisms.

Язык: Английский

---

Multimodal mapping of regional brain vulnerability to focal cortical dysplasia

Brain, Год журнала: 2023, Номер 146(8), С. 3404 - 3415

Опубликована: Фев. 28, 2023

Abstract Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations FCD distribution with cytoarchitecture, gene expression organizational axes may offer complementary insights into processes predispose given regions to harbour FCD. We mapped MRI FCDs 337 patients collected from 13 sites worldwide. then determined its (i) cytoarchitectural features using histological atlases by Von Economo Koskinas BigBrain; (ii) whole-brain spatiotemporal dynamics prenatal adulthood stages Allen Human Brain Atlas PsychENCODE BrainSpan; (iii) macroscale organization. lesions were preferentially located prefrontal fronto-limbic cortices typified low neuron density, large soma thick grey matter. Transcriptomic uncovered component related neuroglial proliferation differentiation, likely accounting dysplastic makeup, postnatal synaptogenesis circuit organization, possibly contributing circuit-level hyperexcitability. showed strong association anterior region antero-posterior axis derived heritability analysis interregional structural covariance thickness, but not functional hierarchical axes. Reliability all results was confirmed through resampling techniques. Multimodal organization indicate neurogenesis be key points vulnerability lobe Concordant causal role atypical growth, our FCD-vulnerable display properties indicative earlier termination initiation cell growth. They also potential contribution aberrant development epileptogenicity.

Язык: Английский

---

Gene regulatory landscape of cerebral cortex folding

Science Advances, Год журнала: 2024, Номер 10(23)

Опубликована: Июнь 5, 2024

Folding of the cerebral cortex is a key aspect mammalian brain development and evolution, defects are linked to severe neurological disorders. Primary folding occurs in highly stereotyped patterns that predefined cortical germinal zones by transcriptomic protomap. The gene regulatory landscape governing emergence this protomap remains unknown. We characterized spatiotemporal dynamics expression active epigenetic (H3K27ac) across prospective folds fissures ferret. Our results show begins emerge at early embryonic stages, it involves cell-fate signaling pathways. H3K27ac reveals developmental restriction engages known regulators, including transcription factor Cux2 . Manipulating progenitors changed their proliferation pattern ferret, caused selective transcriptional changes as revealed single-cell RNA sequencing analyses. findings highlight relevance mechanisms defining folding.

Язык: Английский

---

Cytoskeleton-modulating nanomaterials and their therapeutic potentials

Advanced Drug Delivery Reviews, Год журнала: 2024, Номер 211, С. 115362 - 115362

Опубликована: Июнь 19, 2024

Язык: Английский

---