INTRODUCTION: SORCS2 is one of five proteins that constitute the Vps10p-domain, or sortilin, receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Studies in mice implicate SORCS2 in learning and memory functions, and in the cellular response to stress. We have discovered a novel role for SORCS2 in DNA double-strand break (DSB) formation (Gospodinova et al., 2021). We have shown that loss of the receptor in mice is associated with elevated DSB levels in the dentate gyrus, an area involved in learning and memory. In addition, knocking out SORCS2 in a human neuronal cell line led to increased DSB formation and reduced neuronal viability. DNA damage is linked to age-related cognitive decline, and transient neuronal DSBs also occur during learning and memory formation.
THE PROJECT: The aims of the project are to determine the causes of the DSBs and the impact of SORCS2 loss on the cell. SORCS2 is implicated in neuronal activity, NMDAR trafficking and oxidative stress. The student will perform experiments to investigate whether deficits in these processes underlie the increased numbers of DSBs in the neurons lacking SORCS2. In parallel, the student will investigate the impact of SORCS2 loss on the cell. For example, molecular cell profiling (or cell painting) which provides a multiparametric phenotypic signature via the simultaneous application of fluorogenic protein stains that label multiple cellular structures and subcellular organelles, will be combined with automated high content imaging to extract ~1000 cellular features (various measures of size, shape, texture, intensity etc). These data can be used to create a machine learning model to enable an unbiased classification of cellular phenotypes in a high throughput manner. Thus the project will lead to greater understanding of functions implicated in learning and memory processes and age-related cognitive decline. TRAINING AND ENVIRONMENT: The student will gain skills in laboratory techniques, including: culture of neuronal precursors; neuronal differentiation; morphological and functional assays. Full training in programming, machine learning and statistical analysis will be provided. The student will also develop their communication skills and their ability to evaluate both the literature and their own data critically. The supervisors are based in the Institute for Genetics and Cancer (IGC) where there are over a hundred postgraduate students and a thriving postgraduate society which organises career talks, social events and an annual scientific retreat.
