Multi-omics study reveals differential expression and phosphorylation of autophagy-related proteins in autism spectrum disorder

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 29, 2025

Our multi-omics study investigated the molecular mechanisms underlying autism spectrum disorder (ASD) using Shank3Δ4–22 and Cntnap2−/− mouse models. Through global- phospho- proteomics of cortex, we focused on shared changes found that autophagy was particularly affected in both Global identified a small number differentially expressed proteins significantly impact postsynaptic components synaptic function, including key pathways such as mTOR signaling. Phosphoproteomics revealed unique phosphorylation sites autophagy-related ULK2, RB1CC1, ATG16L1, ATG9, suggesting altered patterns contribute to impaired autophagic flux ASD. SH-SY5Y cells with SHANK3 gene deletion showed elevated LC3-II p62 levels, indicating autophagosome accumulation initiation, while reduced level lysosomal activity marker LAMP1 suggested autophagosome-lysosome fusion. The highlights involvement reactive nitrogen species nitric oxide (NO) disruption. Importantly, inhibition neuronal NO synthase (nNOS) by 7-NI normalized markers levels primary cultured neurons. We have previously shown nNOS improved behavioral phenotypes reveals differential expression ASD but further investigation is needed prove full underscores need for examination into functional consequences sites, which may offer potential novel therapeutic targets treatment.

Language: Английский

Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer’s disease mouse models

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 26, 2025

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by early molecular events that influence progression. Still, mechanisms caused different mutations of AD are not understood. We have performed a multidisciplinary study to investigate and compare stages pathology in two transgenic mouse models: P301S 5xFAD. Using SNOTRAP-based mass spectrometry, we assessed changes S-nitrosylation, nitric oxide-mediated post-translational modification, proteins both models during their juvenile age. The increased levels 3-nitrotyrosine confirmed nitrosative stress mutant mice. Systems biology analysis revealed shared processes between models, particularly γ-aminobutyric acid (GABA)ergic glutamatergic neurotransmission processes. In model, identified 273 S-nitrosylated (SNOed) cortex, with 244 uniquely SNOed diseased 5xFAD 309 were identified. found altered expression glutamate/GABA-related markers cortex hippocampus models. Additionally, phosphorylation mTOR signaling components hyperactivation this pathway Conversely, mice showed no significant except for elevated ribosomal protein S6 cortex. Our findings key stages. These could serve as potential biomarkers therapeutic targets early-stage AD.

Language: Английский

Oxidative Stress Response and NRF2 Signaling Pathway in Autism Spectrum Disorder

Redox Biology, Journal Year: 2025, Volume and Issue: 83, P. 103661 - 103661

Published: May 2, 2025

Language: Английский