Investigating the secretome of glia in health and disease

Glia are a major and diverse class of cells, and each glial subtype is specialised to carry out distinct roles, important in maintaining homeostasis and effective functioning of the nervous system. In order to carry out these functions, glia respond to, and secrete, a range of molecules. In addition to maintaining homeostasis, glia have also been linked to neurodegenerative diseases such as Alzheimer's disease (AD), where they are believed to become reactive and contribute to neuroinflammation. A key feature of this reactive gliosis is the secretion of inflammatory protein mediators. Although in some cases this can be protective, in other instances, the secretion of inflammatory mediators can be harmful, thus contributing to AD pathology. In addition, various types of RNA can also be secreted through extracellular vesicle secretion or via ribonucleoprotein complexes, and there is some evidence linking extracellular RNA to AD. At present, there remains a limited understanding of the global secretome of glial subtypes in terms of their proteomic and RNA-based composition, and potential changes in secretome composition in AD. This research aims to address this by using proximity labelling-based assays to study glial secretomes under different conditions such as comparisons of secretomes from mono-cultures of glial subtypes with co-cultures of glial subtypes and during different stages of AD progression. Downstream analysis of secretome composition will be conducted by carrying out mass spectrometry and proximity-CLIP. An enhanced understanding of the glial secretome and changes linked to disease will provide better insight into glial biology more generally. Ultimately, this may also lead to the identification of novel biomarkers and therapeutic targets for the detection and treatment of AD.