Unraveling the role of neuregulin-mediated astrocytes-OPCs axis in the pathogenesis of age-related macular degeneration and Parkinson’s disease

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

Published: March 1, 2025

Age-related macular degeneration (AMD) and Parkinson's disease (PD) are prevalent debilitating conditions that lead to irreversible blindness dyskinesia, respectively. Emerging evidences imply retinal abnormalities may serve as early indicators for monitoring PD. This study endeavors explore the complex interactions focus on their shared molecular pathological mechanisms. We employed a comprehensive approach by integrating single-cell RNA sequencing (scRNA-seq) datasets, obtained from dry AMD retinas PD brain tissues, along with Weighted Gene Co-expression Network Analysis (WGCNA)-related computational analysis. Set Enrichment (GSEA) was conducted analyze PD-related genes within ganglion cells in AMD. Cell-cell chat utilized predict intercellular communication signaling pathways. Module eigengenes (MEs) were calculated identify specific gene modules. Dysregulation of PALLD, FYN ZMZ1 cell structural abnormalities, impaired mitochondrial functions, increased susceptibility neuroinflammation, contributing progression. Additionally, this highlighted an astrocyte–oligodendrocyte precursor (OPCs) axis mediated Neuregulin (NRG), which is hypothesized influence neuroinflammatory processes characteristic pathogenesis. Notably, ME-salmon module associated dysregulation exhibited strong positive correlation ME-blue module, linked neurodegenerative impairment, ME-yellow related dysfunction. The investigation astrocytes-OPCs axis, NRG pathway advances our understanding intricate biological underpinning research underscores critical importance about exploring glial-related interactions, providing valuable insights into potential novel therapeutic approaches these diseases.

Language: Английский

The multivariate genetic architecture of psychiatric and insulin resistance multimorbidity

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

Published: Oct. 2, 2024

Abstract Psychiatric disorders frequently co-occur with insulin resistance (IR)-related conditions, including obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS). Although pairwise genetic correlations have been observed, the shared genetics underlying this multimorbidity remains underexplored. Here, we investigate joint architecture of psychiatric-IR multimorbidity, explore tissue-specific gene expression associations, identify potential biological mechanisms repurposable drugs. We applied genomic structural equation modeling (SEM) to genome-wide association study (GWAS) data (N=9,725–933,970) from five psychiatric (attention-deficit/hyperactivity disorder, anorexia nervosa, major depressive obsessive-compulsive schizophrenia) three IR-related conditions (MetS, T2DM). Factor analyses revealed a 2-factor solution, where one factors was composed by all (excluding (the Psych-IR factor), representing these IR-conditions. This factor showed inferior temporal, lateral occipital, total cortical brain surface areas. A multivariate GWAS identified 150 risk loci 366 associated genes (128 novel). The significant gene-set associations included binding Notch signaling pathways, while gene-property tissue implicated cerebellum, cortex, pituitary gland, particularly involving during prenatal development stages. Transcriptome-wide SEM (T-SEM) assessed 499 (191 novel), MHC-related genes. Drug repurposing analysis using PharmOmics suggested six candidates, memantine rosiglitazone. Associated derived T-SEM results were combined for enrichment analyses, which highlighted involvement chr16p11.2 region, BDNF signaling, lipid metabolism. offers novel insights into providing foundation future research on precision medicine prevention approaches.

Language: Английский

Loss of Zmiz1 in mice leads to impaired cortical development and autistic-like behaviors

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

Published: Aug. 18, 2024

De novo mutations in transcriptional regulators are emerging as key risk factors contributing to the etiology of neurodevelopmental disorders. Human genetic studies have recently identified ZMIZ1 and its de causal a syndrome strongly associated with intellectual disability, autism, ADHD, microcephaly, other developmental anomalies. However, role ZMIZ brain development or how cause neurological phenotypes is unknown. Here, we generated forebrain-specific Zmiz1 mutant mouse model that develops abnormalities, including cortical corpus callosum dysgenesis, abnormal differentiation upper-layer neurons. Behaviorally, mice show alterations motor activity, anxiety, communication, social interactions strong sex differences, resembling autism. Molecularly, deficiency leads transcriptomic changes disrupting neurogenesis, neuron programs, synaptic signaling. We Zmiz1-mediated downstream regulation factors, Lhx2, Auts2, EfnB2. Importantly, reactivation EfnB2 pathway by exogenous EFNB2 recombinant protein rescues dendritic outgrowth deficits Overall, our vivo findings provide insight into function reveal mechanistic underpinnings syndrome, thereby providing valuable information relevant future on this disorder.

Language: Английский