Scope: Prion diseases are infectious diseases affecting humans and animals. They are caused by mis-folding of a normal cellular protein (the prion protein PrP) into infectious forms (prions), which then propagate themselves by templating more mis-folding events. Reactive oxygen/nitrogen species (ROS/RNS) are formed as byproducts of many cellular processes and can be used as signalling intermediates within the cell. Oxidative stress occurs when the balance between production and detoxification is tipped in favour of increased reactive species, resulting in damage to the cellular components. Our researched aims to investigate the relationships between PrP, prions and prion disease with ROS to generate a significant understanding of both PrP function and prion disease. Research materials, equipment and methods: In the past year we have generated human cerebral organoids for analyzing prion infection and the influence of hereditary mutations within the prion gene on neuronal health. We have purchased new equipment, including an electrophysiology apparatus suitable for organoid/brain slice and cell monolayer analyses and well as an incubator to ensure climate control during these experiments and an automated plate microscope station to analyse changes within the organoids. Research accomplishments: In the conducted experiments we have: identified a new pathway by which PrP may influence adult neurogenesis; generated a murine 3D culture model of brain tissue populated with microglia; discovered a previously unknown function for a PrP cleavage fragment in activation of microglia; begun the development of human cerebral organoid cultures for studying infectious prion disease; and analysed the influence of a hereditary mutation within the prion gene on ROS production and oxidative stress in cerebral organoid cultures.
| Collins, Steven J; Tumpach, Carolin; Groveman, Bradley R et al. (2018) Prion protein cleavage fragments regulate adult neural stem cell quiescence through redox modulation of mitochondrial fission and SOD2 expression. Cell Mol Life Sci 75:3231-3249 |
| Haigh, Cathryn L (2017) Cellular Analysis of Adult Neural Stem Cells for Investigating Prion Biology. Methods Mol Biol 1658:133-145 |
| Lawson, Victoria A; Tumpach, Carolin; Haigh, Cathryn L et al. (2017) In Vivo-Near Infrared Imaging of Neurodegeneration. Methods Mol Biol 1658:253-262 |
| Collins, Steven J; Haigh, Cathryn L (2017) Simplified Murine 3D Neuronal Cultures for Investigating Neuronal Activity and Neurodegeneration. Cell Biochem Biophys 75:3-13 |
