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Emma Bardsley won two prizes: BHF CRE Annual Symposium 2016: 19/9/2016 - Runner Up Poster Prize and OXION Annual Symposium 2016: 30/9/2016 - Winner of the Journal of General Physiology Poster Prize
An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
The ALPK3 gene encodes alpha-protein kinase 3, a cardiac pseudo-kinase of unknown function. Heterozygous truncating variants (ALPK3tv) can cause dominant adult-onset hypertrophic cardiomyopathy (HCM). Here we confirm an excess of ALPK3tv in sarcomere-gene negative HCM patients. Moreover, we generated a novel knock-in mouse model carrying an ALPK3tv (K201X). Homozygous animals displayed hypertrophy and systolic dysfunction. Heterozygous animals demonstrated no obvious baseline; however, they had an aggravated hypertrophic response upon chronic adrenergic challenge. Isolated, unloaded cardiomyocytes from heterozygous and homozygous mice showed reduced basal sarcomere length with prolonged relaxation, whilst calcium transients showed increased diastolic calcium levels. Protein kinase A-mediated phosphorylation, including that of cardiac troponin I, was significantly decreased. In agreement with the cellular HCM phenotype, reduced ratios of myosin heads in the super-relaxed state were measured. Contractile and calcium handling defects were partly corrected by treatment with mavacamten, a novel myosin inhibitor. For the first time with a non-sarcomere HCM variant, we have demonstrated hallmark changes in cardiac contractility and calcium handling. Mavacamten is able to partially rescue the cellular phenotype, hence could be beneficial to HCM patients with ALPK3tv. Moreover, our data points at a potential role of ALPK3 as a modulator of protein kinase A signalling.
Axonal regulation of dopamine transmission by striatal neuromodulators
Striatal dopamine release can be modulated by diverse neuromodulators acting throughout the full anatomical extent of dopamine neurons, from dendrites and soma in the midbrain to axons in the striatum. Besides influencing somatodendritic integration and generation of action potentials by dopamine neurons, neuromodulators act on axons to shape axonal excitability and neurotransmitter release probability. Mesostriatal dopamine axons are immensely arborized, forming thousands of branches per neuron and 105 potential release sites per axonal tree, comprising more than 99% of the surface of the neuron. Dopamine axons therefore offer strategic sites for the regulation of dopamine output by striatal neuromodulators that will then shape dopamine function and dysfunction, and potentially offer therapeutic opportunities for treating dopaminergic disorders. Here, we summarize current knowledge of the striatal neuromodulators and corresponding receptors that influence dopamine release and their underlying circuits where known.
Understanding human dopamine neuron biology in Parkinson's patient cells
Human-induced pluripotent stem cell (hiPSC) technology has revolutionized Parkinson's disease (PD) research, offering opportunities for disease modeling, drug discovery, and personalized medicine. In this chapter, we summarize the impact of hiPSC-derived dopamine neurons (DaNs) on understanding various aspects of PD. This includes exploring PD dopamine neuron biology within the context of voltage-gated calcium channels and electrophysiology, emphasizing the role of calcium channels in neuronal vulnerability and in regulating dopamine release. We address findings related to α-synuclein pathology, highlighting its aggregation, secretion, and intracellular interactions. We also look into the details of the main PD pathology-related organelles: lysosomes, mitochondria, and the endoplasmic reticulum (ER). Lysosomal pathology is investigated, encompassing GBA1-related PD phenotypes, pH regulation, lysosomal calcium channels, and autophagy. Mitochondrial dysfunction is summarized in terms of bioenergetics, α-synuclein/mitochondria interplay, and the mitophagy pathway. We examine ER-related pathology through ER stress and calcium regulation, and the ER-mitochondria contact sites are discussed as a pivotal link between mitochondria and the ER. Finally, we provide a summary of the integration of CRISPR technology into hiPSC-PD research, with a specific focus on its potential in target identification, drug discovery, and therapeutic interventions for dopamine neuron pathology.
Costs of Underfunding Brain Development.
BACKGROUND: Healthcare costs are rising at an exponential rate. Given the constraints of limited resources, it is essential to make informed decisions about priorities to ensure the best possible health outcomes globally. The history of medicine illustrates how these priorities have shifted over time - from early focus on infectious diseases to later emphasis on noncommunicable conditions such as metabolic disorders. Today, neurodegenerative diseases and aging brain are the forefront of medical research, as these conditions profoundly affect individuals, families, and society. SUMMARY: One in three people will experience a mental health disorder in their lifetime, yet it is not widely recognized that many of these conditions may have origins in pre-birth experiences and early life influences. Disruptions in progenitor proliferation, neuronal and glial migration, and differentiation during prenatal development can contribute to lifelong neurodevelopmental abnormalities. Despite the fundamental importance of brain development, most of the neuroscience funding is allocated to studying neurodegeneration, such as dementia and Parkinson's disease, while early life influences remain underexplored. Crucially, the impact of developmental factors begins even before conception. Environmental risks extend beyond direct maternal exposures during pregnancy; they include cumulative parental exposure to teratogenic agents affecting both male and female gametes, as well as early life environmental exposures affecting newborns, infants, and children. These influences are complex yet highly relevant to long-term health outcomes. KEY MESSAGES: We urge greater recognition of the developmental origins of disease and advocate for increased investment in preventive strategies. These include lifestyle modifications, dietary improvements, targeted supplementation, regular exercise, and minimizing exposure to environmental pollutants. Addressing these factors proactively could yield profound benefits for both individual and public health.
Nitric oxide promotes cysteine N-degron proteolysis through control of oxygen availability
Selected proteins containing an N-terminal cysteine (Nt-Cys) are subjected to rapid, O 2 -dependent proteolysis via the Cys/Arg-branch of the N-degron pathway. Cysteine dioxygenation is catalyzed in mammalian cells by 2-aminoethanethiol dioxygenase (ADO), an enzyme that manifests extreme O 2 sensitivity. The canonical substrates of this pathway in mammalia are the regulators of G-protein signaling 4, 5, and 16, as well as interleukin-32. In addition to operating as an O 2 -sensing mechanism, this pathway has previously been described as a sensor of nitric oxide (NO), with robust effects on substrate stability upon modulation of NO bioavailability being widely demonstrated. Despite this, no mechanism to describe the action of NO on the Cys/Arg N-degron pathway has yet been substantiated. We demonstrate that NO can regulate the stability of Cys N-degron substrates indirectly via the regulation of ADO cosubstrate availability. Through competitive, O 2 -dependent inhibition of cytochrome C oxidase, NO can substantially modify cellular O 2 consumption rate and, in doing so, alter the availability of O 2 for Nt-Cys dioxygenation. We show that this increase in O 2 availability in response to NO exposure is sufficient to alter both dynamic and steady-state ADO substrate levels. It is likely that this mechanism operates to couple O 2 supply and mitochondrial respiration with responses to G-protein-coupled receptor stimulation.
Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.
The number of patients with heart failure is expected to rise sharply owing to ageing populations, poor dietary habits, unhealthy lifestyles and improved survival rates from conditions such as hypertension and myocardial infarction. Heart failure is classified into two main types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). These forms fundamentally differ, especially in how metabolism is regulated, but they also have shared features such as mitochondrial dysfunction. HFrEF is typically driven by neuroendocrine activation and mechanical strain, which demands a higher ATP production to sustain cardiac contraction. However, the primary energy source in a healthy heart (fatty acid β-oxidation) is often suppressed in HFrEF. Although glucose uptake increases in HFrEF, mitochondrial dysfunction disrupts glucose oxidation, and glycolysis and ketone oxidation only partially compensate for this imbalance. Conversely, HFpEF, particularly in individuals with metabolic diseases, such as obesity or type 2 diabetes mellitus, results from both mechanical and metabolic overload. Elevated glucose and lipid levels overwhelm normal metabolic pathways, leading to an accumulation of harmful metabolic byproducts that impair mitochondrial and cellular function. In this Review, we explore how disruptions in cardiac metabolism are not only markers of heart failure but also key drivers of disease progression. We also examine how metabolic intermediates influence signalling pathways that modify proteins and regulate gene expression in the heart. The growing recognition of the role of metabolic alterations in heart failure has led to groundbreaking treatments that target these metabolic disruptions, offering new hope for these patients.
Changes in sensorimotor network dynamics in resting-state recordings in Parkinson's disease.
Non-invasive recordings of magnetoencephalography have been used for developing biomarkers for neural changes associated with Parkinson's disease that can be measured across the entire course of the disease. These studies, however, have yielded inconsistent findings. Here, we investigated whether analysing motor cortical activity within the context of large-scale brain network activity provides a more sensitive marker of changes in Parkinson's disease using magnetoencephalography. We extracted motor cortical beta power and beta bursts from resting-state magnetoencephalography scans of patients with Parkinson's disease (N = 28) and well-matched healthy controls (N = 36). To situate beta bursts in their brain network contexts, we used a time-delay-embedded hidden Markov model to extract brain network activity and investigated co-occurrence patterns between brain networks and beta bursts. Parkinson's disease was associated with decreased beta power in motor cortical power spectra, but no significant differences in motor cortical beta-burst dynamics occurred when using a conventional beta-burst analysis. Dynamics of a large-scale sensorimotor network extracted with the time-delay-embedded hidden Markov model approach revealed significant decreases in the occurrence of this network with Parkinson's disease. By comparing conventional burst and time-delay-embedded hidden Markov model state occurrences, we observed that motor beta bursts occurred during both sensorimotor and non-sensorimotor network activations. When using the large-scale network information provided by the time-delay-embedded hidden Markov model to focus on bursts that were active during sensorimotor network activations, significant decreases in burst dynamics could be observed in patients with Parkinson's disease. In conclusion, our findings suggest that decreased motor cortical beta power in Parkinson's disease is prominently associated with changes in sensorimotor network dynamics using magnetoencephalography. Thus, investigating large-scale networks or considering the large-scale network context of motor cortical activations may be crucial for identifying alterations in the sensorimotor network that are prevalent in Parkinson's disease and might help resolve contradicting findings in the literature.
The effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability: A randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects.
BACKGROUND: Chronic pain is a leading cause of disability globally, with limited treatment options and frequent adverse effects. The IMI-PainCare-BioPain project aimed to enhance analgesic drug development by standardizing biomarkers. This study, IMI2-PainCare-BioPain-RCT1, evaluated the effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability in healthy subjects through a randomized, double-blind, placebo-controlled crossover trial. METHODS: The study included 43 healthy participants aged 18-45 years. Participants underwent four treatment periods where they received single doses of lacosamide (200 mg), pregabalin (150 mg), tapentadol (100 mg), or placebo. High-frequency stimulation was applied to induce hyperalgesia. The two primary endpoints were changes in Strength Duration Time Constant (SDTC) in large sensory and motor fibers between lacosamide and placebo periods at the first post-dose timepoint compared to baseline (60 min). Other predefined endpoints included recovery cycle, threshold electrotonus (TEd), and S2 accommodation as well as effects of pregabalin and tapentadol. RESULTS: Lacosamide statistically significantly reduced SDTC in large sensory fibers (mean reduction 0.04 (95% CI 0.01-0.08), p = 0.012) and in motor fibers (mean reduction 0.04 (95% CI 0.00-0.07), p = 0.039) but had no effect on small sensory fibers at the first timepoint compared to placebo. There were no effects of pregabalin and tapentadol on SDTC. Of other predefined endpoints, lacosamide produced statistically significant changes in subexcitability, S2 accommodation TEd(peak), and TEd40(Accom) in large sensory fibers. No statistically significant changes were observed in refractoriness, relative refractory period, or accommodation half-time at the first timepoint compared to placebo. CONCLUSIONS: This study demonstrates that nerve excitability testing can detect pharmacodynamic effects on large myelinated fibers in healthy subjects. Lacosamide statistically significantly reduced peripheral nerve excitability, particularly in large sensory fibers.
Defective Olfactomedin-2 connects adipocyte dysfunction to obesity.
Olfactomedin-2 (OLFM2) is a pleiotropic glycoprotein emerging as a regulator of energy homeostasis. We here show the expression of OLFM2 to be adipocyte-specific and inversely associated with obesity. OLFM2 levels increase during adipogenesis and are suppressed in inflamed adipocytes. Functionally, OLFM2 deficiency impairs adipocyte differentiation, while its over-production enhances the adipogenic transformation of fat cell progenitors. Loss and gain of function experiments revealed that OLFM2 modulates key metabolic and structural pathways, including PPAR signaling, citrate cycle, fatty acid degradation, axon guidance and focal adhesion in 3T3 cell lines and primary human adipocytes. On the molecular level, OLFM2 deficiency in differentiated adipocytes predominantly downregulates genes involved in cell cycle. Extending these findings in vivo, both whole-body Olfm2 knockout and adipose-specific Olfm2 depletion in mice resulted in impaired adipose cell cycle gene expression, with the latter also displaying fat mass accretion and metabolic dysfunction. Collectively, our results underscore a critical role for OLFM2 in adipocyte biology, and support a causative link between reduced adipose OLFM2 and the pathophysiology of obesity.
Compartmentalisation in cAMP signalling: A phase separation perspective.
Cells rely on precise spatiotemporal control of signalling pathways to ensure functional specificity. The compartmentalisation of cyclic AMP (cAMP) and protein kinase A (PKA) signalling enables distinct cellular responses within a crowded cytoplasmic space. Traditionally, compartmentalisation has been attributed to PKA anchoring, phosphodiesterase-mediated cAMP degradation, and restricted cAMP diffusion. Emerging evidence suggests that liquid-liquid phase separation (LLPS) can play a significant role in organising cAMP signalling. LLPS has been implicated in receptor clustering, cyclic nucleotide synthesis, effector activation, signal termination, and offers a dynamic mechanism for spatially restricting cAMP activity. Notably, PKA RIα condensates appear to act as cAMP reservoirs, modulating local cAMP availability and phosphodiesterase-mediated degradation. Disrupting LLPS-mediated condensation of cAMP/PKA pathway components has been linked to cancer and neurodegeneration, pointing to physiological relevance. This review explores current evidence of LLPS in cAMP signalling, highlighting implications for signal compartmentalisation and functional specificity.
Extracellular Vesicles as Targeted Communicators in Complementary Medical Treatments.
The supposed meridians of traditional oriental medicine have been a cause of conflict between traditional and modern medical science. A possible resolution has been proposed: That extracellular vesicles, including exosomes, may be the transmitters of traditional therapies such as massage and acupuncture. This article develops that idea by proposing that the pathways between surface and deep structures may be laid down during the embryonic migration of cells from one region of the developing body to distant regions. This hypothesis depends on the proven targeting of vesicular communication via cell surface binding molecules and their complementary binding sites on target cells. The hypothesis is therefore experimentally testable. The article also draws attention to a strong analogy with Charles Darwin's theory of pangenesis for particulate communication between the soma and germline.
How the Central Dogma and the Theory of Selfish Genes Misled Evolutionary and Medical Sciences in Understanding Multi-factorial Diseases
This synthesis article deconstructs the incorrect interpretations of the Central Dogma of Molecular Biology in popular accounts of Selfish Gene Theory in evolutionary biology and in genomics. “Selfish” in the theory is invalid whether interpreted literally or metaphorically. This deep misinterpretation of twentieth century biology, emphasising the primacy of genes in functionality, has encouraged the search for the genetic origins of major multi-factorial diseases, even in the face of continuing failure of genomics to provide the route to prediction or cures for those common fatal diseases. Reliance on The Human Genome Project for such cures has led medical science into an expensive impasse. It is time to bury the scientific dogmas of the twentieth century. There is no place in science for dogmas of any kind. What we need are functional therapies through understanding the functional networks that control genes and their evolution. We present a new diagrammatic way of representing the causal interactions between functional physiological networks and the chemical processes represented by the Central Dogma. It then becomes evident that there are many ways in which the activity and nucleotide composition of DNA can be varied.
Amyloid-β disrupts APP-regulated protein aggregation and dissociation from recycling endosomal membranes.
Secretory proteins aggregate into non-soluble dense-core granules in recycling endosome-like compartments prior to regulated release. By contrast, aberrantly processed, secreted amyloid-β (Aβ) peptides derived from amyloid precursor protein (APP) form pathological extracellular amyloidogenic aggregations in late-stage Alzheimer's disease (AD). By examining living Drosophila prostate-like secondary cells, we show that both APP and Aβ peptides affect normal biogenesis of dense-core granules. These cells generate dense-core granules and secreted nanovesicles called Rab11-exosomes via evolutionarily conserved mechanisms within highly enlarged secretory compartments with recycling endosomal identity. The fly APP homologue, APP-like (APPL), associates with these vesicles and the compartmental limiting membrane, from where its extracellular domain modulates protein aggregation. Proteolytic release of this domain permits mini-aggregates to coalesce into a large central dense-core granule. Mutant Aβ expression disrupts this process and compartment motility, and increases aberrant lysosomal targeting, mirroring previously unexplained early-stage pathological events in AD. It also promotes cell-to-cell propagation of these endolysosomal defects, again phenocopying changes observed in AD. Our data therefore demonstrate physiological roles for APP in membrane-dependent protein aggregation, involving molecular mechanisms, which when disrupted by Aβ peptides, trigger Alzheimer's disease-relevant pathologies.
Kir6.2 channel activity is regulated by interaction of transmembrane domains 1 and 2 through I167 in the bundle-crossing gate.
ATP-sensitive potassium (KATP) channel in pancreatic β-cells is composed of four pore-forming inward rectifier potassium (Kir) 6.2 subunits and four regulatory sulfonylurea receptor (SUR) 1 subunits and regulate insulin secretion. Kir6.2 consists of a N-terminal region, an outer transmembrane helix (TM1), an intramembrane region that functions as a potassium selectivity filter, an inner transmembrane helix (TM2) that forms a bundle-crossing gate, and a C-terminal cytoplasmic domain. Mutations in the Kir6.2 subunit can cause neonatal diabetes with severe neurological features (DEND syndrome). The DEND syndrome-inducing I167L mutation of Kir6.2 increases the open probability (Po) of the KATP channel. To investigate the gating mechanism impacted by this mutation in Kir6.2 alone, we used C-terminus-truncated Kir6.2 channels to ascertain the impact of I167 mutations on Po in Kir6.2 channels in the absence of SUR1. We found that I167L and I167F mutations showed an increased Po while the Po of other mutations (I167A, I167V) were unchanged when compared to wild-type channels. By mutating residues in TM1 (W68, L72, F75) that may interact with I167, we found that a double mutation of I167L and F75A normalized the Po. These results would suggest that I167 may play an important role in stabilizing the open state of Kir6.2 channels.