Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cerebral organoids DOI Creative Commons
Tatsuya Osaki, Chloé Delépine, Yuma Osako

et al.

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

Published: Aug. 10, 2024

Summary Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, disease severity varies depending on location type of mutation. Here, we focused neuronal activity syndrome patient-derived organoids, analyzing two types MeCP2 mutations – a missense mutation (R306C) truncating (V247X) - using calcium imaging three-photon microscopy. Compared to isogenic controls, found abnormal altered network function based graph theoretic analyses, V247X impacting functional responses connectivity more severely than R306C mutations. These paralleled EEG data obtained patients comparable Labeling DLX promoter-driven inhibitory neurons demonstrated differences excitatory Transcriptomic analyses revealed HDAC2-associated impairment decreased GABA A receptor expression organoids. findings demonstrate mutation-specific mechanisms vulnerability suggest targeted strategies for their treatment.

Language: Английский

Functional neurogenomics in autism spectrum disorders: A decade of progress DOI
Lucy Bicks, Daniel H. Geschwind

Current Opinion in Neurobiology, Journal Year: 2024, Volume and Issue: 86, P. 102858 - 102858

Published: March 27, 2024

Language: Английский

Citations

9
Potential for New Therapeutic Approaches by Targeting Lactate and pH Mediated Epigenetic Dysregulation in Major Mental Diseases DOI Creative Commons
Shabnam Nohesara, Hamid M. Abdolmaleky, Sam Thiagalingam

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(2), P. 457 - 457

Published: Feb. 18, 2024

Multiple lines of evidence have shown that lactate-mediated pH alterations in the brains patients with neuropsychiatric diseases such as schizophrenia (SCZ), Alzheimer’s disease (AD) and autism may be attributed to mitochondrial dysfunction changes energy metabolism. While neuronal activity is associated reduction brain pH, astrocytes are responsible for rebalancing maintain equilibrium. As lactate level main determinant activities impacted by due binding protons (H+) various types proteins, altering their structure function non-neuronal cells brain. Lactate could affect diverse epigenetic modifications, including histone lactylation, which linked acetylation DNA methylation. In this review, we discuss importance homeostasis normal function, role an essential regulatory molecule its contributions abnormalities diseases, shed light on lactate-based pH-modulating therapies targeting modifications. conclusion, attempt highlight potentials challenges translating lactate-pH-modulating clinics treatment diseases.

Language: Английский

Citations

8
Mecp2 knock-out astrocytes affect synaptogenesis by interleukin 6 dependent mechanisms DOI Creative Commons
Elena Albizzati,

Martina Breccia,

Elena Florio

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109296 - 109296

Published: Feb. 23, 2024

Synaptic abnormalities are a hallmark of several neurological diseases, and clarification the underlying mechanisms represents crucial step toward development therapeutic strategies. Rett syndrome (RTT) is rare neurodevelopmental disorder, mainly affecting females, caused by mutations in X-linked methyl-CpG-binding protein 2 (

Language: Английский

Citations

7
Harnessing the potential of human induced pluripotent stem cells, functional assays and machine learning for neurodevelopmental disorders DOI Creative Commons
Ziqin Yang,

Nicole A. Teaney,

Elizabeth D. Buttermore

et al.

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 18

Published: Jan. 8, 2025

Neurodevelopmental disorders (NDDs) affect 4.7% of the global population and are associated with delays in brain development a spectrum impairments that can lead to lifelong disability even mortality. Identification biomarkers for accurate diagnosis medications effective treatment lacking, part due historical use preclinical model systems do not translate well clinic neurological disorders, such as rodents heterologous cell lines. Human-induced pluripotent stem cells (hiPSCs) promising vitro system modeling NDDs, providing opportunities understand mechanisms driving NDDs human neurons. Functional assays, including patch clamping, multielectrode array, imaging-based popular tools employed hiPSC disease models investigation. Recent progress machine learning (ML) algorithms also presents unprecedented advance NDD research process. In this review, we compare two-dimensional three-dimensional formats modeling, discuss applications functional offer insights on incorporating ML into hiPSC-based drug screening.

Language: Английский

Citations

1
The methyl-CpG-binding protein 2 (Mecp2) regulates the hypothalamic mitochondrial function and white adipose tissue lipid metabolism DOI
Nuria Llontop,

Cristián Mancilla,

Patricia Ojeda-Provoste

et al.

Life Sciences, Journal Year: 2025, Volume and Issue: unknown, P. 123478 - 123478

Published: Feb. 1, 2025

Language: Английский

Citations

1
iPSC-derived healthy human astrocytes selectively load miRNAs targeting neuronal genes into extracellular vesicles DOI Creative Commons
Sara Gordillo-Sampedro, Lina Antounians, Wei Wei

et al.

Molecular and Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 129, P. 103933 - 103933

Published: April 23, 2024

Astrocytes are in constant communication with neurons during the establishment and maturation of functional networks developing brain. release extracellular vesicles (EVs) containing microRNA (miRNA) cargo that regulates transcript stability recipient cells. Astrocyte released factors thought to be involved neurodevelopmental disorders. Healthy astrocytes partially rescue Rett Syndrome (RTT) neuron function. EVs isolated from stem cell progeny also correct aspects RTT. cross blood-brain barrier (BBB) their is found peripheral blood which may allow non-invasive detection EV as biomarkers produced by healthy astrocytes. Here we characterize miRNA sequence motifs human astrocyte derived (ADEVs). First, induced Pluripotent Stem Cells (iPSC) were differentiated into Neural Progenitor (NPCs) subsequently using a rapid differentiation protocol. iPSC expressed specific markers, displayed intracellular calcium transients secreted ADEVs. miRNAs identified RNA-Seq on ADEVs target gene pathway analysis detected brain immune related terms. The profile was consistent identity, included approximately 80 relatively depleted suggestive passive loading. About 120 enriched motif discovered binding sites for RNA proteins FUS, SRSF7 CELF5. miR-483-5p most significantly This MECP2 expression has been differentially samples RTT patients. Our results identify potential selectively sorted implicate protein dependent mechanisms

Language: Английский

Citations

6
Variable expression of MECP2, CDKL5, and FMR1 in the human brain: Implications for gene restorative therapies DOI Creative Commons

Antonino Zito,

Jeannie T. Lee

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(9)

Published: Feb. 22, 2024

and

Language: Английский

Citations

5
Mitochondrial dysfunction and increased reactive oxygen species production in MECP2 mutant astrocytes and their impact on neurons DOI Creative Commons
Danielle L. Tomasello, M. Inmaculada Barrasa, David Mankus

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Sept. 4, 2024

Language: Английский

Citations

5
Neural precursor cells rescue symptoms of Rett syndrome by activation of the Interferon γ pathway DOI Creative Commons
Angelisa Frasca, Federica Miramondi, Erica Butti

et al.

EMBO Molecular Medicine, Journal Year: 2024, Volume and Issue: 16(12), P. 3218 - 3246

Published: Sept. 20, 2024

The beneficial effects of Neural Precursor Cell (NPC) transplantation in several neurological disorders are well established and they generally mediated by the secretion immunomodulatory neurotrophic molecules. We therefore investigated whether Rett syndrome (RTT), that represents first cause severe intellectual disability girls, might benefit from NPC-based therapy. Using vitro co-cultures, we demonstrate that, sensing pathological context, NPC-secreted factors induce recovery morphological synaptic defects typical Mecp2 deficient neurons. In vivo, prove intracerebral NPCs RTT mice significantly ameliorates functions. To uncover molecular mechanisms underpinning benefic effects, analyzed transcriptional profile cerebellum transplanted animals, disclosing possible involvement Interferon γ (IFNγ) pathway. Accordingly, report capacity IFNγ to rescue defects, as motor cognitive alterations models, thereby suggesting this pathway a potential therapeutic target for RTT.

Language: Английский

Citations

4
BIOCHEMICAL AND MOLECULAR DETERMINANTS OF THE SUBCLINICAL INFLAMMATORY MECHANISMS IN RETT SYNDROME DOI Creative Commons
Valeria Cordone

Archives of Biochemistry and Biophysics, Journal Year: 2024, Volume and Issue: 757, P. 110046 - 110046

Published: May 28, 2024

To date, Rett syndrome (RTT), a genetic disorder mainly caused by mutations in the X-linked MECP2 gene, is increasingly considered broad-spectrum pathology, instead of just neurodevelopmental disease, due to multitude peripheral co-morbidities and compromised metabolic pathways, affecting patients. The altered molecular processes include an impaired mitochondrial function, perturbed redox homeostasis, chronic subclinical inflammation improper cholesterol metabolism. persistent inflammatory condition was first defined ten years ago, as previously unrecognized feature RTT, playing role pathology progress modulation phenotypical severity. In light this, present work aims at reviewing current knowledge on status immune/inflammatory functions well investigating emerging mechanisms underlying this with special focus latest findings about inflammasome system, autoimmunity responses intestinal micro- mycobiota. On these bases, although further research needed, future therapeutic strategies able re-establish adequate response could represent potential approaches for RTT

Language: Английский

Citations

3