Hedgehog signalling in lifespan determination and neuroprotection in Drosophila (HHneuro).

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The increase in life expectancy worldwide has triggered a dramatic upsurge in neurodegenerative diseases and age-associated effects. On a cellular level, ageing has been associated with various defects, which culminates in a loss of neurons and supporting glial cells in the brain, leading to impairment of neuronal synaptic networks and cognitive function. Therefore, further efforts to promote cellular viability and to unravel the pivotal elements regulating life expectancy are urgently required. In this project, we will use the model system Drosophila melanogaster because it offers a unique platform to address this question due to its relatively short lifespan, genetic amenability and homology to mammals. The overall purpose of the project is to unveil the role of the Drosophila Hedgehog (Hh) signalling pathway in lifespan determination and regulation of aging in the adult brain. Our initial findings indicate that Hh signalling in the nervous system is crucial for longevity in flies and that reactivation of the pathway in glia is sufficient to revert loss-of-Hh phenotypes. Our studies suggest that neuron-cortex glia communication is important for the action of the Hh signalling pathway in the adult brain. We propose that expression and secretion of Hh in neurons activates the Hh signalling cascade in the glial cells, which in turn drives the Ci/Gli-dependent expression of target genes, that mediate integrity of glial cell as well as overall neuroprotection.The project we propose aims to clarify the role of Hh in the adult nervous system and during aging. Initially, we will use up-to-date methodologies to identify the full repertoire of glial specific Hh target genes. This approach will allow us to identify factors mediating neuronal viability and lifespan extension during the ageing process. The analysis of glial specific gene-expression profiles in Hh mutant flies will reveal new basic knowledge and information about the aging process and identify the molecular and cellular defects underlying the shortened longevity of Hh mutant flies. In this sense, we will pay special attention to the Hh-dependent chaperone network, which we have already identified as being involved in this process. In addition, our transcriptome analysis will also highlight neuroprotective factors and genetic pathways that can represent new therapeutic targets to maintain healthy ageing and to delay the onset of age-associated diseases. Besides the role of Hh in aging, we also propose to evaluate the ability of Hh signalling to provide neuroprotection in Drosophila in vivo models for Parkinson´s Disease. To our knowledge, an in-depth analysis of the impact of the Hh pathway on age-dependent homeostasis of the nervous system has never been addressed before and will allow us to gain new insight in the aging process of the adult brain.