Transcript nPad2012 - MRC Mouse Network

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