Investigating the connection between cytoskeletal and mitochondrial homeostasis during ageing

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Project summary (maximum of 4000 characters including spaces/returns) -from original proposal Ageing is accompanied by the decline in motor, sensory and cognitive functions, all severely impacting on human health. It is of high urgency to gain a better understanding of the precise physiological processes underlying neuronal decay during ageing.Various subcellular changes reported for neurons of aged brains include alterations in their microtubule cytoskeleton, changes in mitochondrial localisation or function, inefficient auto-phagosome-lysosome systems, axonal atrophy and deterioration of synapses culminating in neuronal communication deficits. We hypothesise that these changes are not separate and there are causative links between them that follow a stepwise cascade of deterioration. Mitochondria are vital components of synapses, critical for their function by providing energy, metabolites and calcium buffers. It is therefore necessary to maintain a healthy pool of synaptic mitochondria and to ensure the clearance of damaged ones by mitophagy. Mitophagy depends on the autophagosome-lysosome system. Microtubules coordinate the organisation and function of these organelles and the removal of faulty mitochondria. The overarching aim of this work is to study whether microtubule decay can lead to organelle dysfunction and to establish whether this pathological path can explain axonal ageing. Our detailed objectives are:1 To establish the changes in mitochondrial function during neuronal ageing. 2 To investigate whether induced changes in microtubule networks mimic mitochondrial pathologies known from ageing neurons.3 To establish underlying mechanisms linking age-related microtubule perturbation and mitochondrial dysfunction such as the impairment of autophagy/mitophagy.4 To establish whether such alteration contributes to the atrophy of neurons in the ageing brain and study whether microtubules provide a novel target to improve the health of mitochondria. We will use our well-established Drosophila models of neuronal ageing in the brain in vivo and in primary neuronal cultures, as well as mammalian cell models including human cells from young and old individuals. We will study the connection between mitochondrial biology, the autophagosome and the microtubule cytoskeleton in the ageing context employing advanced imaging techniques, cellular and molecular biology, biochemistry and genetics. We aim to provide new explanations for neuronal deterioration in ageing and potential therapeutic strategies.