STXBP1-related disorders (STXBP1-RD) are severe neurodevelopmental conditions associated with synaptic dysfunction, presenting an unmet medical need. P.Arg292Cys (R292C) variant is predicted to alter protein stability and affect interactions involved in synaptic vesicle fusion. This study aimed to screen for interactions between STXBP1-R292C and FDA-approved drugs and natural compounds using in silico and in vivo methods to better understand STXBP1-RD molecular defects. We employed computational structural modeling of STXBP1-R292C, screening and ranking transiently interacting drugs, followed by in vivo phenotypic assessment in a humanized STXBP1-R292C Caenorhabditis elegans (C. elegans) model, and longitudinal clinical observation in a single individual carrying the R292C variant. STXBP1-interacting FDA-approved drugs and natural compounds were identified using in silico analysis based on predicted structural effects. C. elegans locomotion features were quantified using standardized assays. Clinical outcomes were assessed using Vineland-III over 25 months. Computational modeling identified β-nicotinamide mononucleotide (NMN) as one of the lead compounds predicted to transiently stabilize the STXBP1-R292C. We further discovered that NMN was unstable in the R292C mutant STXBP1 pocket and diffused from it, whereas its metabolite the essential coenzyme, nicotinamide adenine dinucleotide (NAD+) remained stable at the binding site throughout the structural simulation. In the C. elegans model, NMN exposure partially, but significantly, modulated locomotion phenotypes toward a wild-type (WT) profile. Vineland-III assessment of a child (2–4 years old) with STXBP1-RD and motor delays showed improved motor domain scores, while other developmental domains displayed limited changes. Our study revealed an association between STXBP1-R292C/STXBP1 and NMN/NAD+ as a lead molecule. At the organismal level, NMN treatment ameliorated motor defects in humanized STXBP1-R292C C. elegans. Lastly, 2-year observations in a child carrying the same mutation suggested an NMN effect on the motor domain, toward a future well-designed clinical trial.
Phosphatidylethanolamine-Binding Protein 1 (PEBP1), also known as Raf Kinase Inhibitory Protein (RKIP), is a widely expressed, highly conserved multifunctional signaling regulator that governs the activity of central signaling pathways including Mitogen-Activated Protein Kinase (MAPK), Nuclear Factor-κB (NF-κB) and G Protein-Coupled Receptors (GPCRs). We note that recent research has uncovered its role as a critical ferroptosis regulator, showing remarkably specific expression and function across different diseases. Here we systematically review the structure and function of PEBP1, focusing on its core mechanisms as a molecular hub in various neurological disorders. We also systematically integrate PEBP1’s multiple roles across these disorders and explain its key position within neuropathological networks by coupling classical signaling pathways with the ferroptosis program. We further examine intervention strategies targeting its functional states and protein interaction networks, and then discuss its clinical translational potential as a therapeutic target, hoping to provide insights for investigations into disease-related mechanisms and the development of therapeutic strategies. Clinical trial number: not applicable.
Alzheimer’s Disease (AD) is marked by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuroinflammation. Cannabidiol (CBD), the major non-psychoactive compound of Cannabis, has demonstrated significant pharmacological potential for the treatment of AD. CBD is known to act on various receptors, including cannabinoid receptor 1 (CB1R) and 2 (CB2R), and peroxisome proliferator activated receptor γ (PPARγ). However, the precise changes in receptor expression in AD, as well as following CBD treatment, remain unclear and inconsistent in literature. To address this, we performed immunohistochemistry and immunoblotting in AD-compromised brain regions, specifically the cortex and the hippocampus. In 5xFAD transgenic (TG) mice, we noted strong deposition of Aβ plaques and glial fibrillary acidic protein (GFAP)- positive astrocytes. However, following CBD treatment, Aβ plaque burden and GFAP accumulation were significantly reduced. We observed increased CB1R expression in the cortex of TG mice, in comparison to age-matched wild-type control mice. CB2R expression changes were insignificant between the two groups, however, following CBD treatment, CB2R expression was significantly increased. Interestingly, we demonstrated PPARγ co-expressed with Aβ plaques in TG mice, and following CBD treatment, PPARγ co-expression increased. Lastly, we demonstrated dysregulations of the PI3K signaling pathway observed in TG mice was ameliorated with CBD treatment. In this study, we attributed the effects of CBD on AD-related biomarkers, particularly decreased Aβ plaque load and neuroinflammation, to the alterations in CB2R and PPARγ expression.
We investigated four regulatory single-nucleotide polymorphisms (SNPs) related to genes previously implicated in the autophagy-lysosomal pathway (rs76904798 and rs6581622 (LRRK2), rs356182 (SNCA), and rs12411216 (GBA1)) in order to assess their association with the clinical heterogeneity of Parkinson’s disease. In a five-year observational study, 518 patients stratified by genotype were analyzed for cognitive, neuropsychiatric, motor, and other clinical signs. The rs356182 (SNCA) variant showed a modest association with disease traits, including significant associations with anxiety (HAMILTON scale). Conversely, the regulatory GBA1-related variant rs12411216 demonstrated a robust pleiotropic association with earlier disease onset, more severe motor impairment, and a broad spectrum of non-motor impairments, including anxiety, depression, impulsive-compulsive behaviors, and cognitive deficits. Longitudinal analyses revealed that patients homozygous for the rs12411216 AA genotype exhibited the most unfavorable progression across multiple domains, suggesting a faster neurocognitive decline. These findings suggest that the distinct pleiotropic effects of the GBA1-related variant rs12411216 contribute significantly to the clinical heterogeneity of PD by shaping unfavorable motor and neuropsychiatric progression trajectories. While the longitudinal design provides new evidence for genotype-dependent patterns, further functional studies are needed to confirm the proposed mechanistic link.
Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is a biologically heterogeneous disorder in which neuronal loss, gliosis, neuroinflammation, and metabolic stress may coexist but are unlikely to be uniformly represented across all patients. To investigate this heterogeneity at the molecular level, we analysed publicly available hippocampal transcriptomic data from individuals with TLE-HS. Our analyses identified three transcriptomically defined putative endotypes within this shared neuropathological diagnosis. These states were associated with distinct molecular programs, including a neuronal/synaptic signalling-dominant profile, an immune- and glia-associated inflammatory state marked by cytokine and complement pathway activity, and a metabolically shifted state characterised by oxidative phosphorylation, reactive oxygen species signalling, and stress-response pathways. Cell-type-associated transcriptional signatures analysis and co-expression network organisation further characterised these transcriptomic endotypes, indicating that glial activation, inflammatory signalling, and mitochondrial/metabolic remodelling are differentially weighted across TLE-HS rather than uniformly present. These findings suggest that TLE-HS comprises partially distinct molecular contexts that may converge on a common histopathological endpoint. By characterising transcriptomically defined states within TLE-HS, this study highlights molecular heterogeneity within a shared histopathological diagnosis.
