👤 Cindy Colson

Alzheimer's disease (AD) is an age-associated neurodegenerative disease marked by progressive cognitive deterioration and beta-amyloid (Aβ) protein buildup, which currently lacks therapeutic interventions to decelerate its pathogenesis. The M1 muscarinic acetylcholine receptor (mAChR) is integral to synaptic plasticity and memory processes and has emerged as a critical target for ameliorating AD-associated cognitive deficits. Although M1 mAChR agonists have pro-cognitive potential, their clinical application is limited by significant cholinergic side effects. Our recent findings demonstrate that VU0486846, an M1 mAChR positive allosteric modulator (PAM) devoid of cholinergic toxicity, exhibits therapeutic benefits in a female APPswe/PSEN1ΔE9 (APP/PS1) Alzheimer's disease mouse model. This compound reversed memory deficits, alleviated anxiety-like behaviours, reduced Aβ pathology, and attenuated neuroinflammation in female mice. However, its therapeutic potential in male AD models remains to be fully characterized. In this study, we find that VU0486846 treatment restored cognitive function in male APP/PS1 mice, as evidenced by improved performance in the novel object recognition and Morris water maze tasks, and reduced anxiety-like behaviours in the open field test. VU0486846 ameliorates impaired autophagy signaling in the hippocampus, however, it does not alter hippocampal Aβ oligomer or plaque burden, despite decreasing BACE1 expression. These findings suggest that VU0486846 exerts behavioural and cognitive benefits via Aβ-independent mechanism(s). Collectively, this study highlights the therapeutic potential of VU0486846 in modulating AD pathophysiology, albeit via sex-specific signaling pathways. Show less

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a leading cause of hypertrophic cardiomyopathy (HCM). Although most cMyBP-C mutations produce truncated proteins and cause HCM via haploinsufficiency, the mechanisms by which missense mutations result in disease remain poorly understood. Here, we have evaluated three mutations in immunoglobulin-like domains C1 (P161S, Y237S) and C2 (P371R), predicted to be pathogenic for HCM, assessing their effects on cMyBP-C actin-binding function, protein thermal stability, and residue mobility. Using a fluorescence lifetime-based actin-binding assay, we found that N-terminal mutants P161S, Y237S, and P371R enhanced C0-C2 interactions with actin in both unphosphorylated and phosphorylated states, suggesting that the mutations strengthen actin binding and make the binding resistant to phosphorylation-mediated regulation. Differential scanning calorimetry revealed that mutants exhibit destabilized thermal melting profiles with reduced unfolding temperature, energy, and cooperativity. Molecular dynamics simulations indicated that these mutations induce allosteric effects, increasing fluctuations of unstructured loops in C1 or C2 that contain key actin-binding residues. These alterations in protein stability and residue mobility may promote domains to visit binding-competent conformations more frequently, reduce the energetic cost of complex formation, and/or expose actin-interacting interfaces, thereby enhancing C0-C2 binding and contributing to HCM pathogenesis. Show less

Cardiac hypertrophy is one of the most common genetic heart disorders and considered a risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) pathway plays a key regulatory function in cardiovascular physiology and pathology in hypertrophy. AZD2014 is a small-molecule ATP competitive mTOR inhibitor working on both mTORC1 and mTORC2 complexes. Little is known about the therapeutic effects of AZD2014 in cardiac hypertrophy and its underlying mechanism. Here, AZD2014 is examined in in vitro model of phenylephrine (PE)-induced human cardiomyocyte hypertrophy and a myosin-binding protein-C (Mybpc3)-targeted knockout (KO) mouse model of cardiac hypertrophy. Our results demonstrate that cardiomyocytes treated with AZD2014 retain the normal phenotype and AZD2014 attenuates cardiac hypertrophy in the Mybpc3-KO mouse model through inhibition of dual mTORC1 and mTORC2, which in turn results in the down-regulation of the Akt/mTOR signaling pathway. Show less

Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex. Using Drosophila and mouse embryonic stem cells, we characterise a recruitment hierarchy, where NSL-deposited histone acetylation enables BRD4 recruitment for transcription of constitutively active genes. Transcriptome analyses in Koolen-de Vries patient-derived fibroblasts reveals perturbations with a cellular homeostasis signature that are evoked by the NSL complex/BRD4 axis. We propose that BRD4 represents a conserved bridge between the NSL complex and transcription activation, and provide a new perspective in the understanding of their functions in healthy and diseased states. Show less