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Neurodegenerative processes of ageing and disease nPad Aims of the consortium • Identify key genes and proteins involved in triggering neurodegeneration in vivo. • Examine contribution of neuronal, synaptic and glial dysfunction to neurodegeneration. • Assess biomarkers of cognition and behaviour capable of tracking neurodegeneration. • Study impact of stress, infection and age on neurodegenerative processes. • Identify common and distinct molecular mechanisms underlying neurodegeneration. • Develop strategies for blocking neurodegenerative processes. The People University of Edinburgh The Roslin Institute & R(D)SVS: Prof Jean Manson, Dr Rona Barron, Prof Tom Freeman, Dr Andrew Gill, Dr Barry McColl , Prof Kim Summers, Dr Tom Wishart Centre for Cognitive and Neural System: Prof Richard Morris, Dr Emma Wood Centre for Neuroregeneration: Prof Peter Brophy, Dr Liliana Minichiello, Dr Karen Horsburgh Human Cognitive Neuroscience, Psychology: Prof Sergio Della Sala Centre for Integrative Physiology: Prof Tom Gillingwater, Prof Richard Ribchester, Prof David Wyllie, Prof Giles Hardingham, Dr Mandy Jackson Centre for Clinical Brain Sciences: Prof Siddharthan Chandran, Prof Seth Grant, Prof Joanna Wardlaw Centre for Regenerative Medicine: Prof Charles ffrench Constant (CfC) The National Creutzfeldt-Jakob Disease Research and Surveillance Unit: Prof James Ironside, Prof Richard Knight , Prof Robert Will Centre for Cardiovascular Sciences: Prof Jonathan Seckl , Prof Megan C Holmes, Dr Joyce Yau Centre for Cognitive Ageing and Cognitive Epidemiology: Prof Ian Deary, Prof John Starr University of St Andrews School of Biology: Prof Frank Gunn-Moore The Expertise Identifying and analysing disorders of the brain, spinal cord, eye, peripheral nervous system and muscle using a range of morphological, molecular, behavioural and functional approaches. The Tools Microscopy (including confocal and electron microscopy), Neurophysiology (including in vitro electrophysiology and synaptic physiology), Molecular biology (including proteomic and gene expression screens), mouse behavioural models of learning and memory Additional Resources •Access to unique human ageing cohorts •Access to banks of human tissues from normal individuals and patients with a wide variety of disorders •Current strategic award bid to Wellcome for a major centre for Comparative Pathology Rationale for prioritising genes • Candidate genes from studies of human patient cohorts and mouse models of neurodegenerative disease to define targets for knockouts. • Examination of publicly available gene expression data sets to discover genes that are expressed in neurons and are important in synaptic function. • Evidence that chosen genes may be important in neurodegenerative disease from human studies or mouse models, in particular those with an identified role at the early stages of disease. Dissecting the early events in neurodegeneration 0 50 100 150 200 injection abnormal PrP gliosis loss of synapses & axon terminals, abnormal LTP neuron loss 250 clinical disease, neuronal dysfunction control 30d.p.i 98dpi 150d.p.i 126dpi Jan Fraser and Debbie Brown terminal disease Pre-synaptic Post-synaptic Tom Gillingwater Tom Gillingwater 126dpi Multiple cell types respond to disease neurones microglia astrocytes Connective tissue cells Macrophages Astrocytes Cell division and protein synthesis Neuronal cells Kim Summers Our approach We expect the knockouts of targets described here will alter the early part of the process of neurodegeneration Our phenotypic analysis will be designed to use the full range of expertise within the consortium to analyse neurodegenerative progression through: •studies on behavioural phenotype induced by the knockout; •examining the influence of the knockout on acute or chronic neurodegenerative process; •analysing phenotypes arising from ageing the knockout mice with and without well characterised stressful interventions (model systems). Funding strategy 1. Production and distribution of mice 2. Pathologic analysis 3. Data gathering and distribution 4. Pilot studies 5. Other studies Genes of interest to the consortium in production Atp1b1 Atp2a2 Avp Cacna1a Clstn1 Clu Cnp Gnao1 Igf1r Mapt Mbp Npas4 Spnb3 Taglin3 Chmp2b Igf1 Vapb Cacna1b Cacna2d1 Col4a3 Comt Dapk1 Dtnbp1 Gabarapl1 Gabarapl2 Htra1 Mthfr Prkar2b Vcp Acta2 Adamts10 Als2 Atxn3 Cd2ap Epha1 Pink1 Slc1a Sod1 Fbxw7 Mapk9 Ndrg4 Rims3
