GM1 Oligosaccharide Ameliorates Rett Syndrome Phenotypes In Vitro and In Vivo via Trk Receptor Activation DOI Open Access
Maria Fazzari, Giulia Lunghi, Emma Veronica Carsana

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(21), P. 11555 - 11555

Published: Oct. 28, 2024

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Despite advancements research, no cure exists due to an incomplete understanding of molecular effects MeCP2 deficiency. Previous studies have identified impaired tropomyosin receptor kinase (Trk) neurotrophin (NTP) signaling and mitochondrial redox imbalances as key drivers pathology. Moreover, altered glycosphingolipid metabolism has been reported RTT. GM1 ganglioside known regulator nervous system, growing evidence indicates its importance maintaining neuronal homeostasis via oligosaccharide chain, coded GM1-OS. GM1-OS directly interacts with Trk receptors on cell surface, triggering neurotrophic neuroprotective pathways neurons. In this study, we demonstrate that ameliorates RTT deficits Mecp2-null model. restored synaptogenesis reduced oxidative stress Mecp2-knock-out (ko) cortical When administered vivo, mitigated RTT-like symptoms. Our findings indicate were mediated activation neuron’s plasma membrane. Overall, our results highlight promising candidate for treatment.

Language: Английский

Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow DOI Creative Commons
Jacques Fantini, Fodil Azzaz, Coralie Di Scala

et al.

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108797 - 108797

Published: Jan. 1, 2025

The traditional model of protein structure determined by the amino acid sequence is today seriously challenged fact that approximately half human proteome made up proteins do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered (IDPs), are involved numerous physiological functions and associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), type 2 diabetes. Targeting these challenging for two reasons: i) we need to preserve their functions, ii) drug design molecular docking possible due lack reliable starting conditions. Faced this challenge, solutions proposed artificial intelligence (AI) such as AlphaFold clearly unsuitable. Instead, suggest an innovative approach consisting mimicking, short synthetic peptides, conformational flexibility IDPs. which call adaptive derived from domains IDPs become structured after interacting ligand. Adaptive peptides designed aim selectively antagonizing harmful effects IDPs, without targeting them directly but through selected ligands, affecting properties. This"target target, arrow" strategy promised open new route discovery currently undruggable proteins.

Language: Английский

Citations

4
Gangliosides and Cholesterol: Dual Regulators of Neuronal Membrane Framework in Autism Spectrum Disorder DOI Open Access
Borna Puljko,

Marija Štracak,

Svjetlana Kalanj Bognar

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1322 - 1322

Published: Feb. 4, 2025

Autism spectrum disorder (ASD) is a neurodevelopmental with heterogeneous clinical presentation. Diagnosing ASD complex, and the criteria for diagnosis, as well term ASD, have changed during last decades. Diagnosis made based on observation accomplishment of specific diagnostic criteria, while particular biomarker does not yet exist. However, studies universally report disequilibrium in membrane lipid content, pointing to unique neurolipid signature ASD. This review sheds light possible role cholesterol gangliosides, complex glycosphingolipids, development In addition maintaining integrity, neuronal signaling, synaptic plasticity, these lipids play neurotransmitter release calcium signaling. Evidence linking lipidome changes includes low levels, unusual ganglioside metabolic profiles. symptoms may be mitigated therapeutic interventions targeting composition membranes. restoring equilibrium central nervous system remains challenge. underscores need comprehensive research into metabolism uncover practical insights etiology treatment lipidomics emerges major area research.

Language: Английский

Citations

0
Cholesterol-Dependent Serotonin Insertion Controlled by Gangliosides in Model Lipid Membranes DOI Open Access
Jacques Fantini, Fodil Azzaz,

Ryad Bennaï

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 10194 - 10194

Published: Sept. 23, 2024

Serotonin is distinct among synaptic neurotransmitters because it amphipathic and released from vesicles at concentrations superior to its water solubility limit (270 mM in for a of 110 mM). Hence, serotonin mostly aggregated the cleft, due extensive aromatic stacking. This important characteristic has received scant attention, as most representations serotonergic synapse take warranted that molecules are present monomers after vesicle exocytosis. Using combination silico physicochemical approaches new experimental device mimicking conditions, we show aggregates efficiently dissolved by gangliosides (especially GM1) postsynaptic membranes. initial interaction, driven electrostatic forces, attracts insoluble resolves micelles into monomers. also interacts with cholesterol via set CH-π van der Waals interactions. Thus, act together functional serotonin-collecting funnel on brain cell Based this unique mode interaction membranes, propose model transmission takes account post-exocytosis solubilizing effect aggregates.

Language: Английский

Citations

1
GM1 Oligosaccharide Ameliorates Rett Syndrome Phenotypes In Vitro and In Vivo via Trk Receptor Activation DOI Open Access
Maria Fazzari, Giulia Lunghi, Emma Veronica Carsana

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(21), P. 11555 - 11555

Published: Oct. 28, 2024

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Despite advancements research, no cure exists due to an incomplete understanding of molecular effects MeCP2 deficiency. Previous studies have identified impaired tropomyosin receptor kinase (Trk) neurotrophin (NTP) signaling and mitochondrial redox imbalances as key drivers pathology. Moreover, altered glycosphingolipid metabolism has been reported RTT. GM1 ganglioside known regulator nervous system, growing evidence indicates its importance maintaining neuronal homeostasis via oligosaccharide chain, coded GM1-OS. GM1-OS directly interacts with Trk receptors on cell surface, triggering neurotrophic neuroprotective pathways neurons. In this study, we demonstrate that ameliorates RTT deficits Mecp2-null model. restored synaptogenesis reduced oxidative stress Mecp2-knock-out (ko) cortical When administered vivo, mitigated RTT-like symptoms. Our findings indicate were mediated activation neuron’s plasma membrane. Overall, our results highlight promising candidate for treatment.

Language: Английский

Citations

0