CDK13-related disorder, also known as congenital heart defects, dysmorphic facial features and intellectual developmental disorder (CHDFIDD) is associated with mutations in the CDK13 gene encoding transcription-regulating cyclin-dependent kinase 13 (CDK13). Here, we focused on the development of craniofacial structures and analyzed early embryonic stages in CHDFIDD mouse models, with one model comprising a hypomorphic mutation in Cdk13 and exhibiting cleft lip/palate, and another model comprising knockout of Cdk13, featuring a stronger phenotype including midfacial cleft. Cdk13 was found to be physiologically expressed at high levels in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme. We also uncovered that Cdk13 deficiency leads to development of hypoplastic branches of the trigeminal nerve including the maxillary branch. Additionally, we detected significant changes in the expression levels of genes involved in neurogenesis (Ache, Dcx, Mef2c, Neurog1, Ntn1, Pou4f1) within the developing palatal shelves. These results, together with changes in the expression pattern of other key face-specific genes (Fgf8, Foxd1, Msx1, Meis2 and Shh) at early stages in Cdk13 mutant embryos, demonstrate a key role of CDK13 in the regulation of craniofacial morphogenesis.

• MeSH
• cyklin-dependentní kinasy metabolismus   genetika   MeSH
• embryo savčí metabolismus   MeSH
• embryonální vývoj * genetika   MeSH
• fenotyp MeSH
• lebka embryologie   patologie   MeSH
• mentální retardace genetika   MeSH
• modely nemocí na zvířatech * MeSH
• mutace genetika   MeSH
• myši MeSH
• nervus trigeminus embryologie   MeSH
• neurogeneze * genetika   MeSH
• obličej embryologie   abnormality   MeSH
• protein doublecortin MeSH
• rozštěp patra genetika   patologie   embryologie   MeSH
• rozštěp rtu genetika   patologie   embryologie   MeSH
• vývojová regulace genové exprese * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

AIMS: This retrospective non-randomised study aims to identify new and rare fusion partners with USP6 in the setting of nodular fasciitis. It has been proven, that nodular fasciitis can harbour different variants of USP6 fusions, which can be used in routine diagnostics and even determine the biological behaviour of the process. METHODS: A total of 19 cases of nodular fasciitis examined between 2011 and 2022 at Motol University Hospital in Prague were included into this study. Next to the histopathological evaluation, all cases were assessed using immunohistochemistry, RT-PCR and Anchored multiplex RNA methods. Patient's main demographic characteristics and corresponding clinical data were also analysed. RESULTS: This study presents one novel (KIF1A) and five rare examples (TMP4, SPARC, EIF5A, MIR22HG, COL1A2) of fusion partners with USP6 among 19 cases of nodular fasciitis. CONCLUSION: Identification of USP6 fusion partners in nodular fasciitis helps to understand the biology of such lesions. Moreover, it can be useful in routine histopathological practice of soft-tissues diagnostics, especially in preventing possible misdiagnosis of malignancy.

• MeSH
• dospělí MeSH
• fasciitida * genetika   patologie   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genová přestavba * MeSH
• imunohistochemie MeSH
• kineziny genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• retrospektivní studie MeSH
• senioři MeSH
• thiolesterasa ubikvitinu * genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

sou shrnuty biologické hypotézy Alzheimerovy nemoci (AD) založené na poznatcích o patofyziologii AD, které slouží jako východiska pro farmakoterapeutické strategie. Pokroky v poznání úlohy rizikových faktorů a biomarkerů AD v neurodegenerativních procesech umožňují jednak upřesnění stávajících hypotéz nebo tvorbu nových, jednak zlepšení diagnostiky onemocnění, sledování progrese onemocnění a nalezení molekulárních cílů nových léčiv. Kromě amyloidové a tau hypotézy, resp. patologie amyloidu beta a tau proteinu, se při vývoji nových léčiv a studiu mechanismů jejich účinků vychází především z hypotézy mitochondriální, metabolické, neurozánětlivé, oxidačního stresu, synaptoplastické a neurotransmiterové. Významné pro pochopení patofyziologie AD se jeví poznatky o vzájemném propojení, interakcích a synergiích buněčných patologických procesů považovaných za klíčové v hypotézách AD.

Biological hypotheses of Alzheimer ́s disease (AD) based on knowledge about the pathophysiology of AD are summarized, which serve as starting points for pharmacotherapeutic strategies. Advances in the knowledge of the role of risk factors and biomarkers of AD in neurodegenerative processes allow the refinement of existing hypotheses or the generation of new ones, as well as the improvement of disease diagnostics, the monitoring of disease progression, and the discovery of molecular targets for new drugs. In addition to the amyloid and tau hypothesis, respectively the pathology of amyloid beta and tau protein, the mitochondrial, metabolic, neuroinflammatory, oxidative stress, synaptoplastic, and neurotransmitter hypotheses are being used to develop new drugs and to study the mechanisms of their action. Important for the understanding of the pathophysiology of AD is the knowledge about the interrelationships, interactions, and synergies of the cellular pathological processes that are considered to be key in the various AD hypotheses.

• MeSH
• Alzheimerova nemoc * diagnóza   etiologie   patofyziologie   MeSH
• amyloidní beta-protein metabolismus   toxicita   MeSH
• biologické markery analýza   MeSH
• lidé MeSH
• mitochondrie metabolismus   patologie   MeSH
• nervový přenos fyziologie   MeSH
• neuroplasticita fyziologie   MeSH
• proteiny tau metabolismus   toxicita   MeSH
• rizikové faktory MeSH
• signální transdukce fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

The 3-mercaptopyruvate sulfurtransferase (MPST) is a protein persulfidase, occurring mainly in mitochondria. Although function of this protein in cancer cells has been already studied, no clear outcome can be postulated up to now. Therefore, we focused on the determination of function of MPST in colon (HCT116 cells)/colorectal (DLD1 cells) cancers. In silico analysis revealed that in gastrointestinal cancers, MPST together with its binding partners can be either of a high risk or might have a protective effect. Silencing of MPST gene resulted in decreased ATP, while acetyl-CoA levels were elevated. Increased apoptosis was detected in cells with silenced MPST gene, which was accompanied by decrease in mitochondrial membrane potential, but no changes in IP3 receptor's protein. Mitochondria underwent activation of fission and elevated DRP1 expression after MPST silencing. Proliferation and migration of DLD1 and HCT116 cells were markedly affected, showing the importance of MPST protein in colon/colorectal cancer development.

• MeSH
• apoptóza MeSH
• dynaminy metabolismus   genetika   MeSH
• HCT116 buňky MeSH
• kolorektální nádory * metabolismus   patologie   enzymologie   genetika   MeSH
• lidé MeSH
• membránový potenciál mitochondrií MeSH
• mitochondrie metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory tračníku metabolismus   patologie   genetika   enzymologie   MeSH
• pohyb buněk MeSH
• proliferace buněk MeSH
• sulfurtransferasy * metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The transcellular propagation of the aberrantly modified protein tau along the functional brain network is a key hallmark of Alzheimer's disease and related tauopathies. Inoculation-based tau propagation models can recapitulate the stereotypical spread of tau and reproduce various types of tau inclusions linked to specific tauopathy, albeit with varying degrees of fidelity. With this systematic review, we underscore the significance of judicious selection and meticulous functional, biochemical, and biophysical characterization of various tau inocula. Furthermore, we highlight the necessity of choosing suitable animal models and inoculation sites, along with the critical need for validation of fibrillary pathology using confirmatory staining, to accurately recapitulate disease-specific inclusions. As a practical guide, we put forth a framework for establishing a benchmark of inoculation-based tau propagation models that holds promise for use in preclinical testing of disease-modifying drugs.

• MeSH
• Alzheimerova nemoc * patologie   MeSH
• modely nemocí na zvířatech MeSH
• mozek patologie   MeSH
• neurofibrilární klubka patologie   MeSH
• proteiny tau metabolismus   MeSH
• tauopatie * patologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• systematický přehled MeSH

BACKGROUND: Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer's disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood. METHODS: We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. RESULTS: We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. CONCLUSION: Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.

• MeSH
• Alzheimerova nemoc * patologie   MeSH
• krysa rodu rattus MeSH
• metabolismus lipidů MeSH
• modely nemocí na zvířatech MeSH
• mozek metabolismus   MeSH
• myši transgenní MeSH
• myši MeSH
• neurofibrilární klubka metabolismus   MeSH
• potkani transgenní MeSH
• proteiny tau genetika   metabolismus   MeSH
• tauopatie * patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.

• MeSH
• Alzheimerova nemoc * metabolismus   genetika   patologie   MeSH
• amyloidový prekurzorový protein beta * genetika   metabolismus   MeSH
• axonální transport * genetika   MeSH
• axony metabolismus   patologie   MeSH
• dynaktinový komplex metabolismus   genetika   MeSH
• dyneiny metabolismus   MeSH
• endozomy metabolismus   genetika   MeSH
• genetická variace MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• mutace MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive deterioration of upper and lower motor neurons. A definitive diagnostic test or biomarker for ALS is currently unavailable, leading to a diagnostic delay following the onset of initial symptoms. Our study focused on cerebrospinal fluid (CSF) concentrations of clusterin, tau protein, phosphorylated tau protein, and beta-amyloid1-42 in ALS patients and a control group. METHODS: Our study involved 54 ALS patients and 58 control subjects. Among the ALS patients, 14 presented with bulbar-onset ALS, and 40 with limb-onset ALS. We quantified biomarker levels using enzyme-linked immunosorbent assay (ELISA) and compared the results using the Mann-Whitney U-test. RESULTS: Significant elevations in neurodegenerative markers, including tau protein (p < 0.0001), phosphorylated tau protein (p < 0.0001), and clusterin (p = 0.038), were observed in ALS patients compared to controls. Elevated levels of tau protein and phosphorylated tau protein were also noted in both bulbar and limb-onset ALS patients. However, no significant difference was observed for beta-amyloid1-42. ROC analysis identified tau protein (AUC = 0.767) and p-tau protein (AUC = 0.719) as statistically significant predictors for ALS. CONCLUSION: Our study demonstrates that neurodegenerative marker levels indicate an ongoing neurodegenerative process in ALS. Nonetheless, the progression of ALS cannot be predicted solely based on these markers. The discovery of a specific biomarker could potentially complement existing diagnostic criteria for ALS.

• MeSH
• amyotrofická laterální skleróza * diagnóza   MeSH
• biologické markery MeSH
• klusterin MeSH
• lidé MeSH
• opožděná diagnóza MeSH
• proteiny tau MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Bardet-Biedl syndrome (BBS) is an archetypal ciliopathy caused by dysfunction of primary cilia. BBS affects multiple tissues, including the kidney, eye and hypothalamic satiety response. Understanding pan-tissue mechanisms of pathogenesis versus those which are tissue-specific, as well as gauging their associated inter-individual variation owing to genetic background and stochastic processes, is of paramount importance in syndromology. The BBSome is a membrane-trafficking and intraflagellar transport (IFT) adaptor protein complex formed by eight BBS proteins, including BBS1, which is the most commonly mutated gene in BBS. To investigate disease pathogenesis, we generated a series of clonal renal collecting duct IMCD3 cell lines carrying defined biallelic nonsense or frameshift mutations in Bbs1, as well as a panel of matching wild-type CRISPR control clones. Using a phenotypic screen and an unbiased multi-omics approach, we note significant clonal variability for all assays, emphasising the importance of analysing panels of genetically defined clones. Our results suggest that BBS1 is required for the suppression of mesenchymal cell identities as the IMCD3 cell passage number increases. This was associated with a failure to express epithelial cell markers and tight junction formation, which was variable amongst clones. Transcriptomic analysis of hypothalamic preparations from BBS mutant mice, as well as BBS patient fibroblasts, suggested that dysregulation of epithelial-to-mesenchymal transition (EMT) genes is a general predisposing feature of BBS across tissues. Collectively, this work suggests that the dynamic stability of the BBSome is essential for the suppression of mesenchymal cell identities as epithelial cells differentiate.

• MeSH
• Bardetův-Biedlův syndrom * genetika   metabolismus   patologie   MeSH
• cilie metabolismus   MeSH
• lidé MeSH
• myši knockoutované MeSH
• myši MeSH
• proteiny asociované s mikrotubuly metabolismus   MeSH
• proteiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

An increase in phosphorylation of the Tau protein is associated with Alzheimer's disease (AD) progression through unclear molecular mechanisms. In general, phosphorylation modifies the interaction of intrinsically disordered proteins, such as Tau, with other proteins; however, elucidating the structural basis of this regulation mechanism remains challenging. The bridging integrator-1 gene is an AD genetic determinant whose gene product, BIN1, directly interacts with Tau. The proline-rich motif recognized within a Tau(210-240) peptide by the SH3 domain of BIN1 (BIN1 SH3) is defined as 216PTPP219, and this interaction is modulated by phosphorylation. Phosphorylation of T217 within the Tau(210-240) peptide led to a 6-fold reduction in the affinity, while single phosphorylation at either T212, T231, or S235 had no effect on the interaction. Nonetheless, combined phosphorylation of T231 and S235 led to a 3-fold reduction in the affinity, although these phosphorylations are not within the BIN1 SH3-bound region of the Tau peptide. Using nuclear magnetic resonance (NMR) spectroscopy, these phosphorylations were shown to affect the local secondary structure and dynamics of the Tau(210-240) peptide. Models of the (un)phosphorylated peptides were obtained from molecular dynamics (MD) simulation validated by experimental data and showed compaction of the phosphorylated peptide due to increased salt bridge formation. This dynamic folding might indirectly impact the BIN1 SH3 binding by a decreased accessibility of the binding site. Regulation of the binding might thus not only be due to local electrostatic or steric effects from phosphorylation but also to the modification of the conformational properties of Tau.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• Alzheimerova nemoc * metabolismus   MeSH
• fosforylace MeSH
• jaderné proteiny metabolismus   MeSH
• lidé MeSH
• nádorové supresorové proteiny chemie   MeSH
• peptidy chemie   MeSH
• prolin metabolismus   MeSH
• proteiny tau * metabolismus   MeSH
• src homologní domény MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH