The astrocyte α1A-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex.

Noradrenaline (norepinephrine) is known to modulate many physiological functions and behaviors. In this study, we tested to what extent astrocytes, a type of glial cell, participate in noradrenergic signaling in mouse primary visual cortex (V1). Astrocytes are essential partners of neurons in the central nervous system. They are central to brain homeostasis, but also dynamically regulate neuronal activity, notably by relaying and regulating neuromodulator signaling. Indeed, astrocytes express receptors for multiple neuromodulators, including noradrenaline, but the extent to which astrocytes are involved in noradrenergic signaling remains unclear. To test whether astrocytes are involved in noradrenergic neuromodulation in mice, we employed both short hairpin RNA mediated knockdown as well as pharmacological manipulation of the major noradrenaline receptor in astrocytes, the α1A-adrenoreceptor. Using acute brain slices, we found that the astrocytic α1A-adrenoreceptor subtype contributes to the generation of large intracellular Ca2+ signals in visual cortex astrocytes, which are generally thought to underlie astrocyte function. To test if reduced α1A-adrenoreceptor signaling in astrocytes affected the function of neuronal circuits in V1, we used both patch-clamp and field potential recordings. These revealed that noradrenergic signaling through the astrocyte α1A-adrenoreceptor is important to not only modulate synaptic activity but also to regulate plasticity in V1, through the potentiation of synaptic responses in circuits involved in visual information processing.

Unravelling cell type-specific responses to Parkinson's Disease at single cell resolution.

Parkinson's Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nucleus transcriptome analysis of human post-mortem SNpc obtained from 15 sporadic Parkinson's Disease (PD) cases and 14 Controls. Our dataset comprises ∼84K nuclei, representing all major cell types of the brain, allowing us to obtain a transcriptome-level characterization of these cell types. Importantly, we identify multiple subpopulations for each cell type and describe specific gene sets that provide insights into the differing roles of these subpopulations. Our findings reveal a significant decrease in neuronal cells in PD samples, accompanied by an increase in glial cells and T cells. Subpopulation analyses demonstrate a significant depletion of tyrosine hydroxylase (TH) enriched astrocyte, microglia and oligodendrocyte populations in PD samples, as well as TH enriched neurons, which are also depleted. Moreover, marker gene analysis of the depleted subpopulations identified 28 overlapping genes, including those associated with dopamine metabolism (e.g., ALDH1A1, SLC6A3 & SLC18A2). Overall, our study provides a valuable resource for understanding the molecular mechanisms involved in dopaminergic neuron degeneration and glial responses in PD, highlighting the existence of novel subpopulations and cell type-specific gene sets.

Combination of ligand and structure based virtual screening approaches for the discovery of potential PARP1 inhibitors.

Poly (ADP-ribose) polymerase 1 (PARP1) has high therapeutic value as biomolecular target for research and development of small molecules with antineoplastic activity, since it is upregulated in many cancers, especially in ovarian and BRCA 1/2 mutated breast cancers. Decades of investigation of PARP inhibitors (PARPi) have led to the approval of several drug compounds, however clinical application of PARPi in cancer therapy is limited due to a number of factors, including low selectivity, weak affinity and undesired side effects. Thus, identification of novel drug-like chemical compounds with alternatives to the known PARPi chemical scaffolds, binding modes and interaction patterns with amino acid residues in the active site is of high therapeutic importance. In this study we applied a combination of ligand- and structure-based virtual screening approaches with the goal of identification of novel potential PARPi.

Identification of Novel Potential VEGFR-2 Inhibitors Using a Combination of Computational Methods for Drug Discovery.

The vascular endothelial growth factor receptor 2 (VEGFR-2) is largely recognized as a potent therapeutic molecular target for the development of angiogenesis-related tumor treatment. Tumor growth, metastasis and multidrug resistance highly depends on the angiogenesis and drug discovery of the potential small molecules targeting VEGFR-2, with the potential anti-angiogenic activity being of high interest to anti-cancer research. Multiple small molecule inhibitors of the VEGFR-2 are approved for the treatment of different type of cancers, with one of the most recent, tivozanib, being approved by the FDA for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). However, the endogenous and acquired resistance of the protein, toxicity of compounds and wide range of side effects still remain critical issues, which lead to the short-term clinical effects and failure of antiangiogenic drugs. We applied a combination of computational methods and approaches for drug design and discovery with the goal of finding novel, potential and small molecule inhibitors of VEGFR2, as alternatives to the known inhibitors' chemical scaffolds and components. From studying several of these compounds, the derivatives of pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione in particular were identified.