Glial cells in the ageing retina lose control of their genetic instructions, and this project will test whether that loss actively drives the death of neighbouring neurons. The retina is part of the central nervous system, and its age-related degeneration mirrors what happens in the brain. Researchers have long focused on neurons themselves, but glial cells—which support neurons—also malfunction with age. This project asks a fundamental question: does glial dysfunction cause neurodegeneration, or is it merely a consequence? The team will use the killifish, a vertebrate that ages rapidly and shows sex differences in retinal decline similar to humans, to track when glial genes go awry relative to neuron death. If glial dysregulation proves to be a driver of neurodegeneration, it would shift the field’s focus toward glial cells as therapeutic targets. This is fundamental science—there is no immediate clinical application—but understanding the sequence of events in ageing could eventually inform strategies to preserve sight or slow neurodegenerative diseases. Past discoveries about glial biology have already reshaped how researchers think about conditions like multiple sclerosis and Alzheimer’s.
View original technical description
Glial cells are known to be crucial support cells for neurons in the central nervous system (CNS). The loss of molecular integrity in aged neurons results in neurodegeneration and loss of function; however, the potential role of glial cells in this process has been largely overlooked. Here, we will explore the kinetics glial dysregulation relative to neurodegeneration and manipulate glial homeostasis pathways in a vertebrate CNS tissue, the retina, to determine whether genetic dysregulation in glia drives age-related neuronal decline. If correct, this will revolutionise our understanding of how altered glial integrity can influence the long-term health of neurons. Ageing is a gradual and irreversible process whereby cell and tissue function declines. The CNS is particularly prone to age-related impairment and neurodegenerative disease. The precise mechanisms driving this age-related decline remain unclear. One of the many mechanisms documented in the ageing CNS is genetic dysregulation, whereby gene expression is altered leading to mis-expression of transcripts. However, the cause and consequence of this dysregulation remains poorly studied. Glial cells directly contact neurons and express key molecules to provide supportive functions, including maintaining homeostasis, sharing trophic factors, and recycling neurotransmitters. Like other cell types, ageing can cause a loss of normal function in glia which reduces their ability to properly maintain a healthy CNS environment, negatively altering their interactions with neighbouring cells, and potentially contributing to neuronal dysfunction and degeneration. We have recently identified several genetic pathways that are progressively dysregulated in glial cells in the ageing retina. Further, we have identified sex-specific differences in retinal degeneration, similar to what occurs in humans, leading to the intriguing potential that genetic dysregulation in the retina may be distinct between the sexes. These observations raise several intriguing questions regarding the basis of age-related neurodegeneration, most importantly: Does glial dysregulation precede neurodegeneration in the retina and does glial dysregulation drive neurodegeneration in the ageing CNS? Unfortunately, studies aiming to address these critical questions are hampered by a lack of a suitable model. The killifish is an eminently suitable model system to study ageing due to rapid ageing, sexual dimorphism, conserved CNS structure, cellular labels and amenability to genetic manipulation. We will take advantage of a well-characterised CNS tissue, the retina, and the rapidly ageing killifish to explore the kinetics of cell-specific degeneration, identify conserved cell-type specific molecular pathways underlying age-related neuronal degeneration and determine whether glial genetic dysregulation can drive neurodegeneration in the ageing retina. These studies would be challenging, if not impossible, in any other model system. As such we are eminently positioned to address these key pressing questions in the field of glial biology and ageing. This project aims to: 1) characterise the kinetics of retinal neurodegeneration throughout the life course; 2) Determine sex-specific cellular and genetic changes in the ageing retina; 3) Identify the epigenetic modifications underlying glial genetic dysregulation in ageing; 4) Determine the consequence of glial genetic dysregulation on neurodegeneration in the context of ageing. We will utilise a multi-disciplinary approach to achieve our goals, including cutting-edge multiplex cellular labelling developed in our laboratory, our expertise in semi-super resolution imaging, transcriptomics and epigenomics, robust computational morphometric analyses and genetics. Overall, this proposal will establish the killifish as the preeminent preclinical model to study the ageing retina and support the innovative study of fundamental mechanisms of CNS ageing.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know