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

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 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.

Язык: Английский

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

Current Opinion in Neurobiology, Год журнала: 2024, Номер 86, С. 102858 - 102858

Опубликована: Март 27, 2024

Язык: Английский

Процитировано

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

и другие.

Biomedicines, Год журнала: 2024, Номер 12(2), С. 457 - 457

Опубликована: Фев. 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.

Язык: Английский

Процитировано

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

Martina Breccia,

Elena Florio

и другие.

iScience, Год журнала: 2024, Номер 27(3), С. 109296 - 109296

Опубликована: Фев. 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 (

Язык: Английский

Процитировано

7
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

и другие.

Life Sciences, Год журнала: 2025, Номер unknown, С. 123478 - 123478

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

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

и другие.

Molecular and Cellular Neuroscience, Год журнала: 2024, Номер 129, С. 103933 - 103933

Опубликована: Апрель 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

Язык: Английский

Процитировано

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, Год журнала: 2024, Номер 121(9)

Опубликована: Фев. 22, 2024

and

Язык: Английский

Процитировано

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

и другие.

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Сен. 4, 2024

Язык: Английский

Процитировано

4
Neural precursor cells rescue symptoms of Rett syndrome by activation of the Interferon γ pathway DOI Creative Commons
Angelisa Frasca, Federica Miramondi, Erica Butti

и другие.

EMBO Molecular Medicine, Год журнала: 2024, Номер 16(12), С. 3218 - 3246

Опубликована: Сен. 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.

Язык: Английский

Процитировано

4
Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications DOI Creative Commons
Péter Balicza, András Gézsi,

Mariann Fedor

и другие.

Frontiers in Psychiatry, Год журнала: 2024, Номер 14

Опубликована: Янв. 5, 2024

We present a male patient carrying pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development later experienced severe social anxiety, learning disabilities, cognitive slowing, symptoms associated rigidity. Clinical examinations showed multisystemic involvement. Together elevated ergometric lactate levels, clinical picture suggested disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis revealed involvement metabolic oxidative phosphorylation pathways. Whole-exome sequencing identified variant, can explain both dopamine imbalance in this patient. Mitochondrial previously classical Rett syndrome, we detected related phenotype on multiple consistent levels for first time carrier male. This study further supports importance gene pathways, open gate more personalized therapeutic interventions. Good response highlights role complex syndrome. help identify optimal treatment strategy from transdiagnostic perspective instead diagnostic category.

Язык: Английский

Процитировано

3
Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes DOI
Nicolas Leventoux, Satoru Morimoto, Mitsuru Ishikawa

и другие.

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Май 15, 2024

Язык: Английский

Процитировано

3