Neurodegenerative processes of ageing and disease

nPad

• 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.

Aims of the consortium

The PeopleUniversity of EdinburghThe 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 HorsburghHuman 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 JacksonCentre for Clinical Brain Sciences: Prof Siddharthan Chandran, Prof Seth Grant, Prof Joanna WardlawCentre 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 ExpertiseIdentifying 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

• 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.

Rationale for prioritising genes

injectionterminal disease

0 50 100 150 200 250

abnormal PrP loss of synapses& axon terminals, abnormalLTP

gliosis neuron loss

clinical disease, neuronal

dysfunction

150d.p.i

30d.p.i

control

98dpi

126dpi

Jan Fraser and Debbie Brown

Dissecting the early events in neurodegeneration

Pre-synaptic

Post-synaptic

Tom Gillingwater

126dpi

Tom Gillingwater

microglia astrocytes

neurones

Multiple cell types respond to disease

Neuronal cells

Cell division and protein synthesis

Astrocytes

Macrophages

Connective tissue cells

Kim Summers

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).

Our approach

1. Production and distribution of mice

2. Pathologic analysis

3. Data gathering and distribution

4. Pilot studies

5. Other studies

Funding strategy

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Chmp2b Igf1 VapbCacna1b Cacna2d1 Col4a3 Comt Dapk1 Dtnbp1 Gabarapl1 Gabarapl2Htra1MthfrPrkar2bVcp

Acta2 Adamts10 Als2 Atxn3 Cd2apEpha1Pink1Slc1aSod1Fbxw7Mapk9Ndrg4Rims3

Genes of interest to the consortium in production