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Physiological function of cyclic nucleotide phosphodiesterases in atrial myocytes and their potential as therapeutic targets for atrial fibrillation.
Cyclic nucleotide hydrolyzing phosphodiesterases (PDEs) are key regulators of cyclic nucleotide (e.g., cAMP and cGMP) signaling. Here, we examine the role of PDEs in the physiology of atrial myocytes (AMs), the pathogenesis of atrial fibrillation (AF), and the potential of PDEs as therapeutic targets for AF. PDE1-5 and 8 are present and functional in AMs. PDE2-4 are important regulators of AM contraction but their role beyond atrial contractility is unclear. The role of PDE1,5 and 8 in healthy AMs is unknown but of interest because of their roles in ventricular myocytes. We propose that PDE2-5 and PDE8 are potential targets to prevent the triggering of AF considering their effects on Ca2+ handling and/or electrical activity. PDE1-5 are possible targets to treat patients with paroxysmal or persistent AF caused by pulmonary vein automaticity. PDE8B2 is a possible target for patients with persistent AF due to its altered expression. Research should aim to identify the presence, localization, and function of specific PDE isoforms in human atria. Ultimately, the paucity of PDE isoform-specific small molecule modulators and the difficulty of delivering PDE-targeted medications or therapies to particular cell types limit current research and its application.
Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study
Background: α-synuclein seed amplification assay (SAA) positivity has been proposed as a diagnostic biomarker for Parkinson's disease. However, studies of the prognostic value of this biomarker have been limited to small, single-centre studies over short follow-up periods. We aimed to assess the diagnostic and prognostic value of quantitative CSF α-synuclein SAA kinetic measures in Parkinson's disease. Methods: In this longitudinal cohort study, we collected and analysed data from participants with Parkinson's disease, progressive supranuclear palsy, and healthy controls enrolled in three cohorts: the UK parkinsonism cohort, the Parkinson's Progression Markers Initiative (PPMI) international observational study, and the Tübingen Parkinson's disease cohort. Baseline CSF α-synuclein SAA data and longitudinal clinical data were collected between Jan 1, 2005, and Nov 1, 2023. The following seeding kinetic measures were calculated from the α-synuclein SAA curve for each SAA-positive sample: time to threshold (TTT) for a positive SAA result; maximum Thioflavin T fluorescence during the reaction time (MaxThT); and area under the fluorescence curve during the reaction time (AUC). We compared seeding kinetic measures between sporadic Parkinson's disease and progressive supranuclear palsy, and between sporadic Parkinson's disease and monogenic Parkinson's disease. We used time-to-event analyses to assess the ability of α-synuclein SAA kinetic measures to predict an unfavourable outcome in Parkinson's disease, adjusting for sex, age, and disease duration at SAA testing. Findings: We analysed data from 1631 participants: newly generated data from the UK parkinsonism cohort (Parkinson's disease, n=66; progressive supranuclear palsy, n=52; controls, n=9) and previously generated data from the PPMI (Parkinson's disease, n=1036; controls, n=239) and Tübingen (Parkinson's disease, n=229) cohorts. In the UK parkinsonism cohort, α-synuclein SAA was positive in 63 (96%) of 66 Parkinson's disease samples and eight (15%) of 52 progressive supranuclear palsy samples, with six (75%) of eight positive progressive supranuclear palsy samples having distinct low and slow seeding kinetics (low MaxThT and high TTT) as a marker of Lewy body co-pathology. TTT was faster in GBA1-associated Parkinson's disease compared with sporadic Parkinson's disease in both the PPMI (p=0·04) and Tübingen (p=0·01) cohorts. In the PPMI cohort, after excluding individuals who had an unfavourable outcome at the time of baseline SAA testing, an unfavourable outcome was observed in 593 (73%) of 810 participants with α-synuclein SAA-positive Parkinson's disease during a median follow-up period of 4·5 years (IQR 2–9). TTT at baseline predicted only cognitive decline (Montreal Cognitive Assessment score ≤21) as a component of an unfavourable outcome in Parkinson's disease in both the PPMI (n=824, hazard ratio [HR] 2·36 [95% CI 1·60–3·46], p=0·001) and Tübingen (n=135, 2·17 [1·07–4·41], p=0·03) cohorts. TTT also predicted cognitive decline in a subgroup of participants with Parkinson's disease in the PPMI cohort who were Alzheimer's disease biomarker negative (n=355, HR 1·80 [95% CI 1·03–3·18], p=0·04). Interpretation: Assessing α-synuclein SAA kinetic measures might aid in the diagnostic differentiation of Parkinson's disease from progressive supranuclear palsy with Lewy body co-pathology. Furthermore, faster seeding kinetics are found in GBA1-Parkinson's disease and predict cognitive decline in Parkinson's disease independently of Alzheimer's disease co-pathology. Funding: Medical Research Council, PSP Association. Copyright: © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
A compilation of reported alterations in the cerebrospinal fluid proteome in Alzheimer's disease.
Alzheimer's disease is a multifaceted neurodegenerative disorder, with diverse underlying pathophysiological processes extending beyond amyloid-β and tau accumulation. The heterogeneity of Alzheimer's disease necessitates the identification of a broad array of biomarkers that capture the diverse mechanisms contributing to disease onset and progression. In this study, we systematically compiled and analysed cerebrospinal fluid proteomics data from omics studies utilizing mass spectrometry, Olink, or SomaScan platforms. Systematic literature searches for each platform revealed a total of 264 studies. From this, a set of 18 studies were selected based on sample size, number of markers analysed, and open data availability. We found a total of 1,448 differentially expressed proteins between Alzheimer's disease and amyloid negative controls across these datasets, with 635 being found in more than one study. A 'top' set of 61 differentially expressed proteins were consistently reported in at least six studies. Clustering and functional enrichment analysis of the top differentially expressed proteins indicated involvement in metabolic regulation, glutathione metabolism and proteins of the 14-3-3 family, reflecting importance of reactive oxygen species (ROS) response. Synaptic signalling processes were found to generally be downregulated. We further integrated the top differentially expressed proteins with results from a study on familial Alzheimer's disease cerebrospinal fluid to assess at which stage of disease progression these proteins change, highlighting markers shared between sporadic and familial Alzheimer's disease datasets. Lastly, we examine the overlap of the top differentially expressed proteins between cerebrospinal fluid and brain tissue using a publicly available database. This analysis provides a comprehensive overview of the Alzheimer's disease cerebrospinal fluid proteomic landscape, indicating changes in key pathways and cellular processes associated with Alzheimer's disease pathology. By integrating data from different platforms, we highlight reproducible protein changes that may serve as promising candidates for further biomarker research aimed at improving patient stratification, tracking disease progression, and assessing therapeutic interventions.
Brain MRI signatures across sex and CSF Alzheimer's disease biomarkers.
The relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegenerative effects is not fully understood. This study investigates neurodegeneration patterns across CSF Alzheimer's disease biomarker groups, the association of brain volumes with CSF amyloid and tau status and sex differences in these relationships in a clinical neurology sample. MRI and CSF Alzheimer's disease biomarkers data were analysed in 306 patients of the Mass General Brigham healthcare system aged 50+ (mean age = 68.4 ± 8.8 years; 43.1% female), who had lumbar punctures within 1 year of clinical MRI scans. We first analysed neurodegeneration patterns across four biomarker groups: 60 controls (A-T-&CU; amyloid negative, tau negative, cognitively unimpaired), 25 A+T- (amyloid positive, tau negative), 121 A+T+ (amyloid positive, tau positive) and 100 other dementia (A-T-&CI; amyloid negative, tau negative, cognitively impaired). Second, we examined volumetric associations with amyloid (amyloid positive, tau negative versus control) and tau in the presence of amyloid (amyloid positive, tau positive versus amyloid positive, tau negative) across 52 brain areas. Third, we examined sex differences in these relationships. Finally, we validated core analyses across three independent datasets-NACC (National Alzheimer's Coordinating Center), ADNI (Alzheimer's Disease Neuroimaging Initiative) and EPAD (European Prevention of Alzheimer's Dementia)-totalling 3137 participants, and performed meta-analyses to obtain more robust estimates. We observed distinct neurodegeneration patterns across biomarker groups, with disrupted connectivity (brain volume covariance networks) in amyloid positive and other dementia groups, while amyloid and tau negative, cognitively unimpaired controls exhibited the most connected network. Amyloid was associated with subcortical, cerebellar and brainstem atrophy, with consistent association observations in the thalamus and amygdala across all four datasets. Tau in the presence of amyloid demonstrated general brain shrinkage through enlargement of extracerebral CSF, alongside unexpected ventricle shrinkages. Sex-based analyses revealed that A+T+ (amyloid positive, tau positive) had lower sex differences in connectivity patterns compared with other groups. Sex differences were also noted in amyloid-related ventricular volume changes. This study reveals how amyloid and tau affect brain connectivity and volume across sex and CSF biomarker groups, emphasizing global brain changes and sex differences. By leveraging automated pipelines and advanced MRI and biomarker analyses, we extracted meaningful and replicable findings from heterogeneous clinical samples from real-world data. The meta-analyses across four datasets enhance the generalizability of our results.
Consensus recommendations for hyperpolarized [1-13C]pyruvate MRI multi-center human studies.
MRI of hyperpolarized (HP) [1-13C]pyruvate allows in vivo assessment of metabolism and has translated into human studies across diseases at 15 centers worldwide. To determine consensus on best practice for multi-center studies for development of clinical applications. This paper presents the results of a two-round formal consensus building exercise carried out by experts with HP [1-13C]pyruvate human study experience. Twenty-nine participants from 13 sites brought together expertise in pharmacy methods, MR physics, translational imaging, and data analysis with the goal of providing recommendations and best practice statements on conduct of multi-center human studies of HP [1-13C]pyruvate MRI. Overall, the group reached consensus on approximately two-thirds of 246 statements in the questionnaire, covering HP 13C-pyruvate preparation; MRI system setup, calibration, and phantoms; acquisition and reconstruction; and data analysis and quantification. Consensus was present across categories. Examples include: (i) Different HP pyruvate preparation methods could be used in human studies, but the same release criteria have to be followed; (ii) site qualification and quality assurance must be performed with phantoms and the same field strength must be used, but the rest of the system setup and calibration methods could be determined by individual sites; (iii) the same pulse sequence and reconstruction methods were preferable, but the exact choice should be governed by the anatomical target; (iv) normalized metabolite area-under-curve values and metabolite area under curve were the preferred metabolism metrics. The consensus proces revealed that HP[1-13C] pyruvate MRI as a technology has progressed sufficiently to plan multi-center studies. The work confirmed areas of consensus for multi-center study conduct and identified where further research is required to ascertain best practice.
Maternal iron deficiency perturbs embryonic cardiovascular development in mice.
Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.
Maternal iron deficiency perturbs embryonic cardiovascular development in mice
AbstractCongenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.
Myhre syndrome is caused by dominant-negative dysregulation of SMAD4 and other co-factors.
Myhre syndrome is a connective tissue disorder characterized by congenital cardiovascular, craniofacial, respiratory, skeletal, and cutaneous anomalies as well as intellectual disability and progressive fibrosis. It is caused by germline variants in the transcriptional co-regulator SMAD4 that localize at two positions within the SMAD4 protein, I500 and R496, with I500 V/T/M variants more commonly identified in individuals with Myhre syndrome. Here we assess the functional impact of SMAD4-I500V variant, identified in two previously unpublished individuals with Myhre syndrome, and provide novel insights into the molecular mechanism of SMAD4-I500V dysfunction. We show that SMAD4-I500V can dimerize, but its transcriptional activity is severely compromised. Our data show that SMAD4-I500V acts dominant-negatively on SMAD4 and on receptor-regulated SMADs, affecting transcription of target genes. Furthermore, SMAD4-I500V impacts the transcription and function of crucial developmental transcription regulator, NKX2-5. Overall, our data reveal a dominant-negative model of disease for SMAD4-I500V where the function of SMAD4 encoded on the remaining allele, and of co-factors, are perturbed by the continued heterodimerization of the variant, leading to dysregulation of TGF and BMP signaling. Our findings not only provide novel insights into the mechanism of Myhre syndrome pathogenesis but also extend the current knowledge of how pathogenic variants in SMAD proteins cause disease.
Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: Negative mutation analysis of DLL3, MESP2, HES7, and LFNG.
The spondylocostal dysostoses (SCDs) are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV) and abnormality of the thoracic cage with mal-aligned ribs and often a reduction in rib number. The four known monogenic forms of SCD follow autosomal recessive inheritance, have generalized SDV, a broadly symmetrical thoracic cage, and result from mutations in Notch signaling pathway genes-DLL3, MESP2, LFNG, and HES7. Autosomal dominant (AD) SCD has been reported less often, is very variable, and molecular genetic mechanisms remain elusive. Here, we report a three-generation, non-consanguineous family with four affected individuals demonstrating multiple or generalized SDV. Scoliosis was present and the trunk shortened but the ribs were relatively mildly affected. There were no other significant organ abnormalities, no obvious dysmorphic features, neurodevelopment was normal, and all investigations, including mutation analysis of DLL3, MESP2, LFNG, and HES7, were normal. A non-pathogenic variant was detected in LFNG but it did not segregate with the phenotype. This Macedonian kindred adds to knowledge of AD SCD and to our knowledge is the first to be tested for the four Notch pathway genes known to be associated with SCD.
MEF2 proteins, including MEF2A, are expressed in both muscle and non-muscle cells.
The MEF2 proteins are involved in regulation of many muscle specific genes. Although MEF2 RNAs encoding the MEF2A and MEF2D isoforms are ubiquitously expressed, the presence of MEF2 proteins in non-muscle cell types has been controversial. Here we use a well-characterised antibody in conjunction with DNA binding studies to provide evidence that members of the MEF2 family are widely expressed in the nuclei of cultured cells and are competent to bind DNA. The data show that non-muscle MEF2 complexes contain MEF2A, and that another MEF2 protein, probably MEF2D, is also present. These results suggest that MEF2 proteins fulfil functions in addition to muscle-specific gene expression.
Xenopus laevis transgenesis by sperm nuclear injection.
The stable integration of transgenes into embryos of the frog Xenopus laevis is achieved using the procedure described here. Linear DNA containing the transgene is incorporated randomly into sperm nuclei that have had their membranes disrupted with detergent treatment. Microinjection of these nuclei into unfertilized eggs produces viable embryos that can be screened for activity of the transgene. The proportion of embryos that harbor the transgene varies from 10 to 40% of the total number of surviving embryos. Multiple copies of the transgene can integrate as a concatemer into the sperm genome, and more than one site of DNA integration might occur within resulting animals. Germ cell transmission of the transgene is routine and the procedure is well suited to the production of transgenic reporter frog lines. One day should be allocated for the preparation of the sperm nuclei, which are stored as aliquots for future use. The transgenesis reaction and egg injection take one morning.
Regulation of the tinman homologues in Xenopus embryos.
Vertebrate homologues of the Drosophila tinman transcription factor have been implicated in the processes of specification and differentiation of cardiac mesoderm. In Xenopus three members of this family have been isolated to date. Here we show that the XNkx2-3, Xnkx2-5, and XNkx2-10 genes are expressed in increasingly distinctive patterns in endodermal and mesodermal germ layers through early development, suggesting that their protein products (either individually or in different combinations) perform distinct functions. Using amphibian transgenesis, we find that the expression pattern of one of these genes, XNkx2-5, can be reproduced using transgenes containing only 4.3 kb of promoter sequence. Sequence analysis reveals remarkable conservation between the distalmost 300 bp of the Xenopus promoter and a portion of the AR2 element upstream of the mouse and human Nkx2-5 genes. Interestingly, only the 3' half of this evolutionarily conserved sequence element is required for correct transgene expression in frog embryos. Mutation of conserved GATA sites or a motif resembling the dpp-response element in the Drosophila tinman tinD enhancer dramatically reduces the levels of transgene expression. Finally we show that, despite its activity in Xenopus embryos, in transgenic mice the Xenopus Nkx2-5 promoter is able to drive reporter gene expression only in a limited subset of cells expressing the endogenous gene. This intriguing result suggests that despite evolutionary conservation of some cis-regulatory sequences, the regulatory controls on Nkx2-5 expression have diverged between mammals and amphibians.
Early steps in vertebrate cardiogenesis.
Heart formation provides an excellent model for studying the molecular basis of cell determination in vertebrate embryos. By combining molecular assays with the experimental approaches of classic embryology, a model for the cell signalling events that initiate cardiogenesis is emerging. Studies of chick, amphibian, and fish embryos demonstrate the inductive role of dorso-anterior endoderm in specifying the cardiac fate of adjacent mesoderm. A consequence of this signalling is the onset of cardiomyogenesis and several transcription factors--Nkx2-5-related, HAND, GATA and MEF-2 families--contribute to these events.
Mutation of HES7 in a large extended family with spondylocostal dysostosis and dextrocardia with situs inversus.
Spondylocostal dysotosis (SCD) is a rare developmental congenital abnormality of the axial skeleton. Mutation of genes in the Notch signaling pathway cause SCD types 1-5. Dextrocardia with situs inversus is a rare congenital malformation in which the thoracic and abdominal organs are mirror images of normal. Such laterality defects are associated with gene mutations in the Nodal signaling pathway or cilia assembly or function. We investigated two distantly related individuals with a rare combination of severe segmental defects of the vertebrae (SDV) and dextrocardia with situs inversus. We found that both individuals were homozygous for the same mutation in HES7, and that this mutation caused a significant reduction of HES7 protein function; HES7 mutation causes SCD4. Two other individuals with SDV from two unrelated families were found to be homozygous for the same mutation. Interestingly, although the penetrance of the vertebral defects was complete, only 3/7 had dextrocardia with situs inversus, suggesting randomization of left-right patterning. Two of the affected individuals presented with neural tube malformations including myelomeningocele, spina bifida occulta and/or Chiari II malformation. Such neural tube phenotypes are shared with the originally identified SCD4 patient, but have not been reported in the other forms of SCD. In conclusion, it appears that mutation of HES7 is uniquely associated with defects in vertebral, heart and neural tube formation, and this observation will help provide a discriminatory diagnostic guide in patients with SCD, as well as inform molecular genetic testing.