Exploring the Landscape of Pre- and Post-Synaptic Pediatric Disorders with Epilepsy: A Narrative Review on Molecular Mechanisms Involved

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 11982 - 11982

Опубликована: Ноя. 7, 2024

Neurodevelopmental disorders (NDDs) are a group of conditions affecting brain development, with variable degrees severity and heterogeneous clinical features. They include intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity (ADHD), often coexisting epilepsy, extra-neurological comorbidities, multisystemic involvement. In recent years, next-generation sequencing (NGS) technologies allowed the identification several gene pathogenic variants etiologically related to these in large cohort affected children. These genes encode proteins involved synaptic homeostasis, such as SNARE proteins, implicated calcium-triggered pre-synaptic release neurotransmitters, or channel subunit post-synaptic ionotropic glutamate receptors brain's fast excitatory neurotransmission. this narrative review, we dissected emerged molecular mechanisms NDDs epilepsy due defects pre- transmission. We focused on most recently discovered SNAREopathies AMPA-related synaptopathies.

Язык: Английский

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The GluA1 cytoplasmic tail regulates intracellular AMPA receptor trafficking and synaptic transmission onto dentate gyrus GABAergic interneurons, gating response to novelty

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

Опубликована: Дек. 2, 2024

The GluA1 subunit, encoded by the putative schizophrenia-associated gene GRIA1, is required for activity-regulated AMPA receptor (AMPAR) trafficking, and plays a key role in cognitive affective function. cytoplasmic, carboxy-terminal domain (CTD) most divergent region across AMPAR subunits. CTD has received considerable attention its during long-term potentiation (LTP) at CA1 pyramidal neuron synapses. However, function other synapses and, more broadly, contribution to different GluA1-dependent processes, poorly understood. Here, we used mice with constitutive truncation of dissect regulating localization as well processes. We found that affected subunit levels intracellular trafficking. ΔCTD exhibited no memory deficits, but presented exacerbated novelty-induced hyperlocomotion dentate gyrus granule cell (DG GC) hyperactivity, among behavioral alterations. Mechanistically, EPSCs onto DG GABAergic interneurons were significantly reduced, presumably underlying, least part, observed changes neuronal activity behavior. In summary, this study dissociates CTD-dependent from CTD-independent functions, unveiling crucial hub type-specific manner.

Язык: Английский

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Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant

Clinical Genetics, Год журнала: 2024, Номер 106(4), С. 427 - 436

Опубликована: Июнь 18, 2024

Abstract Ionotropic glutamate receptors (iGluRs), specifically α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPARs), play a crucial role in orchestrating excitatory neurotransmission the brain. AMPARs are intricate assemblies of subunits encoded by four paralogous genes: GRIA1‐4 . Functional studies have established that rare GRIA variants can alter AMPAR currents leading to loss‐ or gain‐of‐function. Patients affected heterozygous tend family specific and only few recurrent been reported. We deep‐phenotyped cohort comprising eight unrelated children adults, harboring well‐established disease‐causing GRIA1 variant (NM_001114183.1: c.1906G>A, p.(Ala636Thr)). Recurrent symptoms included motor and/or language delay, mild–severe intellectual disability, behavioral psychiatric comorbidities, hypotonia epilepsy. also report challenges social skills, autonomy, living work situation, occupational levels. Furthermore, we compared their clinical manifestations relation those documented patients presenting with at analogous positions within genes. This study provides unprecedented details on neurodevelopmental outcomes, cognitive abilities, seizure profiles, abnormalities associated p.(Ala636Thr) refining broadening phenotype.

Язык: Английский

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ELFN1 is a new extracellular matrix (ECM)-associated protein

Life Sciences, Год журнала: 2024, Номер 352, С. 122900 - 122900

Опубликована: Июль 9, 2024

Язык: Английский

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Insights into Asparaginase Allergic Responses: Exploring Pharmacogenetic Influences

Pharmaceutics, Год журнала: 2024, Номер 16(9), С. 1134 - 1134

Опубликована: Авг. 28, 2024

Acute lymphoblastic leukemia represents the most prevalent childhood cancer. Modern chemotherapy has significantly improved outcomes, achieving EFS rates of 80% and OS nearing 90% in developed nations, while developing regions, remain below 50%, highlighting disparities, this difference is due to several factors. Genetic variability plays a role these drug response presenting single-nucleotide variations (SNVs). Pharmacogenetic research aims pinpoint SNVs early treatment predict specific responses effectively. This review explore advancements pharmacogenetics associated with asparaginase (ASNase). ASNase crucial ALL available three formulations: E. coli, Erwinia, PEG ASNase. therapy presents challenges adverse effects, like hypersensitivity reactions. Identifying predictive markers for development beforehand optimizing treatments. Several pharmacogenetic studies have investigated association between risk hypersensitivity. Key genes include GRIA1, NFATC2, CNTO3, ARHGAP28, MYBBP1A, HLA. Studies highlighted associations within Notably, investigations focused on patients treated emphasizing need broader exploration across different formulations. Future investigating variants holds promise advancing our understanding ASNase’s pharmacogenetics.

Язык: Английский

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