Williams G.K., Akkermans J., Lawson M., Syta P., Staelens S., Adhikari M.H., Morton A.J., Nitzsche B., Boltze J., Christou C., Bertoglio D., Ahamed M.

The major goal of our preliminary cross-sectional study is to demonstrate the feasibility and utility of the unique transgenic sheep model of HD (OVT73) in positron emission tomography (PET) imaging. In this first-of-its-kind study, we showed the usefulness and validity of HD sheep model in imaging cerebral glucose metabolism and dopamine uptake using PET imaging. The identification of discrete patterns of metabolic abnormality using [¹⁸F]FDG and decline of [¹⁸F]FDOPA uptake may provide a useful means of quantifying early HD-related changes in these models, particularly in the transition from presymptomatic to early symptomatic phases of HD.

ACS Chemical Neuroscience. October 2024

Lorenzo Morè, Lucia Privitera, Marcia Lopes, J. Simon C. Arthur, Julie C. Lauterborn, Sonia A.L. Corrêa, Bruno G. Frenguelli

One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur. To establish whether MSK1 converts ampakine-induced elevations of BDNF into cognitive enhancement we tested an ampakine (CX929) in male WT mice and in male mice in which the kinase activity of MSK1 was inactivated. We found that MSK1 is required for the ampakine-dependent improvement in spatial reference memory and cognitive flexibility, and for the elevations of BDNF and the plasticity-related protein Arc associated with ampakines and experience. These observations implicate MSK1 as a key enabler of the beneficial effects of ampakines on cognitive function, and furthermore identify MSK1 as a hub for BDNF-elevating nootropic strategies.

Neuropharmacology. 2024

Mireia Montaner, Jessica Denom, Vincent Simon, Wanqing Jiang, Marie K. Holt, Daniel I. Brierley, Claude Rouch, Ewout Foppen, Nadim Kassis, David Jarriault, Dawood Khan, Louise Eygret, Francois Mifsud, David J. Hodson, Johannes Broichhagen, Lukas Van Oudenhove, Xavier Fioramonti, Victor Gault, Daniela Cota, Frank Reimann, Fiona M. Gribble, Stephanie Migrenne-Li, Stefan Trapp, Hirac Gurden & Christophe Magnan

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α₂-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABA_A receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

Nature Communications. August 2024

Jake Brooks, James Everett, Emily Hill, Kharmen Billimoria, Christopher M. Morris, Peter J. Sadler, Neil Telling & Joanna F. Collingwood

Neuromelanin-pigmented neurons of the substantia nigra are selectively lost during the progression of Parkinson’s disease. These neurons accumulate iron in the disease state, and iron-mediated neuron damage is implicated in cell death. Here, scanning transmission x-ray microscopy (STXM) is used to probe iron foci in relation to the surrounding ultrastructure in melanised neurons of human substantia nigra from a confirmed Parkinson’s case. The findings show that STXM is a powerful label-free tool for the in situ, nanoscale chemical characterisation of both organic and inorganic intracellular components. Future applications are likely to shed new light on incompletely understood biochemical mechanisms, such as metal dysregulation and morphological changes to cell nucleoli, that are important in understanding the pathogenesis of Parkinson’s.

Communications Biology. August 2024

Peter Wotherspoon, Hannah Johnston, David J. Hardy, Rachel Holyfield, Soi Bui, Giedrė Ratkevičiūtė, Pooja Sridhar, Jonathan Colburn, Charlotte B. Wilson, Adam Colyer, Benjamin F. Cooper, Jack A. Bryant, Gareth W. Hughes, Phillip J. Stansfeld, Julien R. C. Bergeron & Timothy J. Knowles

The Maintenance of Lipid Asymmetry (Mla) pathway is a multicomponent system found in all gram-negative bacteria that contributes to virulence, vesicle blebbing and preservation of the outer membrane barrier function. Here, we report the structure of E. coli MlaC in complex with the MlaD hexamer in two distinct stoichiometries. Utilising in vivo complementation assays, an in vitro fluorescence-based transport assay, and molecular dynamics simulations, we confirm key residues, identifying the MlaD β6-β7 loop as essential for MlaCD function. We also provide evidence that phospholipids pass between the C-terminal helices of the MlaD hexamer to reach the central pore, providing insight into the trajectory of GPL transfer between MlaC and MlaD.

Nature Communications. July 2024

Okinaka Y, Maeda M, Kataoka Y, Nakagomi T, Doi A, Boltze J, Claussen C, Gul S, Taguchi A

Intravascularly transplanted bone marrow cells, including bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells, transfer water-soluble molecules to cerebral endothelial cells via gap junctions. Following transplantation of BM-MNC, this fosters hippocampal neurogenesis and enhancement of neuronal function. Herein, we report the impact of transplanted BM-MNC on neural stem cells (NSC) in the brain. Surprisingly, direct transfer of water-soluble molecules from transplanted BM-MNC and peripheral mononuclear cells to NSC in the hippocampus was observed already 10 minutes after cell transplantation, and transfer from BM-MNC to GFAP-positive cortical astrocytes was also observed. In-vitro investigations revealed that BM-MNC abolish the expression of HIF1α in astrocytes. We suggest that the transient and direct transfer of water-soluble molecules between cells in circulation and NSC in the brain may be one of the biological mechanisms underlying repair of brain function.

Stem Cells & Development. July 2024