Hedgehog signalling in lifespan determination and neuroprotection in Drosophila
Description: In humans, ageing is accompanied with an increase in prevalence of neurodegenerative diseases (Bishop et al, 2010). On a cellular level, ageing has been associated with various defects which culminates in a loss of irreplaceable cells, including neurons and supporting glial cells in the brain leading to impairment of neuronal synaptic networks and cognitive function (Ouchi et al, 2005; Kraft et al, 2012; Medeiros and LaFerla, 2013). Globally, there is an increased necessity to promote longevity and maintain a viable and healthy adult brain function. Model systems such as Drosophila are used as a valuable paradigm for studies in life span extension, due to its relatively short lifespan, genetic amenability and homology to mammals (Grandison et al, 2009; Broughton et al, 2010). However, only limited information is available about the main pathways involved in maintaining adult brain integrity. The overall purpose of the project is to acquire an in depth insight into how the Drosophila Hedgehog (Hh) signalling pathway is able to promote healthy longevity and maintain the viability of the adult brain during ageing. Our current findings indicate that Hh signalling is involved in lifespan determination as well as in neuroprotection during ageing but the mechanism involved is still unknown. We propose that neuronal expression and secretion of Hh in the adult brain activates the Hh signalling cascade in the glial cells, which subsequently drives the Ci/Gli-dependent transcription of neuroprotective targets, including a chaperone network. One of these chaperones, when expressed in the glia of Hh mutant flies, exerts a potent neuroprotective effect and rescues Hh-dependent shortened longevity, neuronal defects and debilitated locomotion. Importantly, it also rescues longevity/debilitated locomotion in a Parkinson disease (PD) model. Overall, our studies suggest that neuron-cortex glia communication in the adult brain is the mechanism by which the Hh signalling pathway is activated in the glia, which in turn facilitates sustained neuroprotection, possibly through regulation of neuroprotective factors in the glia. The project we propose aims to identify the full repertoire of Hh targets responsible for mediating the maintenance of neuronal viability and healthspan during the ageing process. The analysis of glia specific gene-expression profiles in Hh mutant flies will reveal new basic knowledge and information about the aging process, as well as the neuroprotective factors and genetic pathways that can represent new therapeutic targets to maintain healthy ageing and to delay the onset of age-associated diseases. We also propose to analyze in more details the Hh-dependent chaperone network which provides protection during the ageing process, focusing on their role in maintaining adult brain viability. Finally, we propose to evaluate Hh signaling potential to provide neuroprotection in an a-synuclein-induced PD in vivo model. To our knowledge, the impact of the Hedgehog pathway on age-dependent homeostasis of the nervous system has never been addressed. All the above aims will be addressed by the experiments and contingency plans put forward and expanded upon in the work programme of the project proposal by the complementary technical expertise of the S. Schneuwly (DFG) and P. Thérond (CNRS) Labs.
Funder: Agence Nationale de la Recherche
Amount: €271,800
Funding type: research
Funder scheme: AAPG2017
Start date: 2017-11-01
Investigator: Pascal THEROND
Institution: Université Nice Sophia Antipolis - Institut de biologie de Valrose
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Funded outputs count: 1
Funder award ID: ANR-17-CE14-0041
OpenAlex ID: G4037538346