The CtBP1 protein is a transcriptional regulator that interacts with chromatin-modifying enzymes and modulates gene expression in various cellular pathways. The dominant negative de novo molecular variant c.1024C>T, p.Arg342Trp in the CTBP1 gene is associated with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (HADDTS). Here we present a male patient with a recurrent hotspot mutation in the CTBP1 gene and a phenotype consistent with HADDTS. The patient presented with global developmental delay, floppy infant syndrome, ataxia, intellectual disability with speech disorder, facial dysmorphia, enamel defect, constipation, and cerebellar atrophy on brain imaging. This is the 18 th reported case of this ultra-rare disorder, and the first patient of Polish origin. Diagnosing neurodevelopmental disorders remains challenging; however, modern large-scale genetic tests and a diagnostic approach from genotype to phenotype enable the diagnosis of an increasing number of patients with rare diseases that present non-specifically but have a severe course.

As the second leading cause of death, stroke has a significant impact on public health. Homocysteine (Hcy), a non-essential sulfur-containing amino acid, has recently been found to aggravate brain injury in stroke. This effect is closely associated with oxidative stress (OS), blood-brain barrier (BBB) dysfunction, and endothelial cell damage. Etomidate, originally developed as a sedative, has demonstrated strong protective effects against OS and inflammation. However, its role in stroke remains underexplored. Our research aimed to investigate the potential effects of etomidate in treating Hcy-induced stroke. In C57BL/6 mice, Hcy (0.03 µmol/g, subcutaneous) was administered for one month alongside etomidate (3 mg/kg, intraperitoneal). BBB permeability was assessed via sodium fluorescein diffusion, while OS (GSH, MDA) and inflammation (TNF-a, IL-1b) were measured using spectrophotometry and ELISA. Occludin and KLF2 expression were analyzed by Western blot and immunostaining. In vitro, human brain microvascular endothelial cells (HBMVECs) were treated with Hcy (20 µM) and etomidate (2.5-5 µM), with barrier integrity evaluated via FITC-dextran assay and transepithelial/transendothelial electrical resistance (TEER) measurements. KLF2 knockdown was performed using lentiviral shRNA to confirm its mechanistic role. Hcy-challenged mice exhibited significantly decreased reduced GSH levels, increased MDA, TNF-a, and IL-1b levels, enhanced diffusion of sodium fluorescein, and reduced occludin expression. These changes were notably reversed by etomidate. In vitro, primary HBMVECs were stimulated with 20 µM Hcy, with or without etomidate (2.5 or 5 µM) for 24 hours. Hcy-treated HBMVECs showed significantly increased FITC-dextran intensity, decreased TEER, reduced occludin expression, and diminished KLF2 levels. These effects were notably reversed by etomidate. Moreover, the protective effects of etomidate on Hcy-induced occludin reduction and increased endothelial monolayer permeability were negated by KLF2 inhibition. In conclusion, etomidate exerts protective effects against Hcy-induced BBB disruption by upregulating KLF2.

Progressive degeneration of dopamine neurons in the substantia nigra is the primary pathological abnormality in Parkinson's disease (PD). It has been demonstrated that overactivation of glutamatergic neurons leads to excessive accumulation of intracellular calcium and impairs autophagy. To assess the neuroprotective effects of ifenprodil, rats with 6-hydroxydopamine (6-OHDA)-induced injuries were administered ifenprodil either intraperitoneally (I.P.) or directly into the caudate-putamen (CPU) and substantia nigra pars reticulata (SNr). The results indicate that ifenprodil increases motor function in 6-OHDA-lesioned rats. Furthermore, ifenprodil enhances tyrosine hydroxylase (TH) neuron expression and promotes neuronal autophagy by upregulating beclin-1 and LC3-2 while downregulating P62 and PARP expression. Additionally, ifenprodil may enhance synaptic plasticity by downregulating NR2B-CaMKII and PSD95 expression. A notable improvement was observed in the CPU group. Our study showed that direct delivery of ifenprodil to specific brain regions produced superior therapeutic effects compared to systemic administration in 6-OHDA-lesioned rat models.

Accumulating evidence indicates that pathological interactions between (?) -synuclein (ASN) and tau contribute to the progression of (?) -synucleinopathies; however, the mechanisms linking ASN exposure to tau dysregulation and neuronal cytoskeletal pathology remain incompletely understood. In the present study, we investigated whether bilateral intrastriatal injection of ASN oligomers induces alterations in tau phosphorylation associated with microtubule (MT) abnormalities in the mouse brain. Western blot analyses were performed in the striatum, midbrain, and cortex at 180 days post-injection to assess tau phosphorylation at disease-associated epitopes (Ser199/202, Ser404, and Ser416) together with (?) / (?) -tubulin levels. Ultrastructural changes in neuronal cytoskeletal organisation were evaluated qualitatively using transmission electron microscopy (TEM). ASN exposure induced selective, bidirectional, site- and region-specific changes in tau phosphorylation rather than uniform hyperphosphorylation. Increased p-tau(Ser199/202) levels were observed in the striatum and cortex, whereas p-tau(Ser404) was elevated in the midbrain but decreased in the cortex. No significant changes in p-tau(Ser416) or (?) / (?) -tubulin levels were detected in any analysed brain region. TEM analyses further revealed disrupted neuronal MT organisation, characterised by fragmented and loosely packed MT networks, reduced MT abundance, and occasional loss of cytoskeletal elements accompanied by axonal or synaptic swelling, despite preserved total (?) / (?) -tubulin levels. Collectively, our findings indicate that ASN oligomers induce selective, region-specific dysregulation of tau phosphorylation that co-occurs with neuronal MT disorganisation and cytoskeletal abnormalities. Together, these findings support a link between ASN-induced, site- and region-specific tau dysregulation and neuronal cytoskeletal pathology in (?) -synucleinopathies.

Mucin 1 (MUC1), a transmembrane glycoprotein, is aberrantly expressed in multiple cancers and implicated in tumor progression. This study investigated MUC1 expression in glioma tissues and cell lines, its correlation with tumor malignancy, and the effect of differential expression on patient prognosis. Bioinformatics analysis using the GEPIA database evaluated MUC1 expression in pan-cancer and its effect on the prognosis of glioma patients. Clinical samples from 9 glioma patients with WHO grades II-IV and 2 normal brain tissues with traumatic brain injury controls were analyzed via immunohistochemistry. RT-qPCR and Western blot were used to analyze MUC1 expression in glioblastoma (GBM) cell lines (U251, U87, A172, LN229) and normal human astrocytes (NHA). MUC1 was significantly overexpressed in glioma tissues compared to normal brain tissue (p < 0.05), with higher expression correlating with advanced tumor grade. High MUC1 levels predicted poor patient survival (p < 0.01). GBM cell lines exhibited elevated MUC1 mRNA and protein levels vs. NHA (p < 0.001). MUC1 correlation with glioma malignancy and patient outcomes represents a prognostic biomarker and potential therapeutic target, underscoring its relevance in neuropathology practice.