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Transcript of Synapse Complexity Swartz Foundation Banbury Meeting, CSHL 15 th April 2009 Seth Grant Genes to...
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Synapse Complexity
Swartz FoundationBanbury Meeting, CSHL
15th April 2009
Seth Grant
Genes to Cognition programwww.genes2cognition.org
Wellcome Trust Sanger Institute, Cambridge UK
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MASC
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PSDMASC
Post-Synaptic Proteome
MASC MAGUK Associated Signaling ComplexPSD Post Synaptic Density------------------------------------------------------------------------------------------PSP Post Synaptic Proteome (total set of postsynaptic proteins)
Presynaptic terminal
Postsynaptic terminal
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NR
2
PSD-95fyn
NMDA receptor
Genetic evidence for postsynaptic complexes
Grant, et al, Science. 258, 1903-10. 1992Migaud et al, Nature, 396; 433-439. 1998Sprengel et al, Cell 92, 279-89. 1998
Learning impairmentsPlasticity impairments
MAGUK proteins
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PSD95
NR
Husi et al. Nature Neuroscience, 3 (7), 661-669. 2000.Husi & Grant. J. Neurochem, 77, 281-291. 2001Collins et al, J. Neurochem. 2005Fernandez et al, submitted
Proteomic characterisation of complexes
• 2.5 Mda
• 77 proteins (2000)• 186 (2005)• 158 (2009)• 118 core (2009)
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Migaud et al, Nature, 396; 433-439. 1998; Husi et al, Nature Neuroscience, 2000
synaptic strength gene expressionmRNA turnoverProtein turnover
BehavioursCognition & plasticity
NRC / MASC
2-3 MDa186 proteins
47 genes in human disease48 synaptic plasticity42 rodent behaviour
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Complexity
PSDMASC
PSD 700 -1500 proteins
MASC 77 - 185 proteins
MASC occupies ~10 % of the PSP
- a core subset- same classes of proteins- ideal model of PSP- multiple isolation methods available
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Grant. (2006) Biochemical Society Transactions. 34, 59-63. 2006
Post Synaptic Density 1124ER:microsomes 491Splicesome 311NRC/MASC 186Nucleolus 147Peroxisomes 181Mitochondria 179Phagosomes 140Golgi 81Choroplasts 81Lysosomes 27Exosomes 21
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Is there some logic to this complexity ?
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Pocklington, et al, Molecular Systems Biol 2006.
Molecular Networks: modular protein interaction networks
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upstream
downstream
Upstream and Downstream modules
A useful tool for handling complexity
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Human cortex PSD: 1462 protein network
Alex Bayes, Mark Collins, Louie Van De Lagemaat, Ian Whittle, Jyoti Choudhary
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The origin and evolution of synapses and the brain
Emes et al, Nature Neuroscience 11, 799 (2008)
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6 myr
75 myr
600 myr
1000 myr
Tree of life
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6 myr
75 myr
600 myr
1000 myr
chordates
metazoans
eukaryotes
Origin of the brain
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The first neurons and first brains
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protosynapse
combinations
expansion
Emes et al, Nature Neuroscience 11, 799 (2008)
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570 genes: 186 NRC/MASC; 570 PSD
Number of orthologues compared to mouse
Comparative genomics
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Synapse orthologues in single cell eukaryotes control response to environment
Yeast behaviours:- Environmental responses
- - stress- - nutrients- - pH
143 PSD proteins
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Origin of the brain
synapse first modelneuron first model
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6 myr
75 myr
600 myr
1000 myr
chordates
metazoans
eukaryotes
Origin of the brain
protosynapse
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Unicellulareukaryotes
Invertebrates Vertebrates
Evolutionary elaboration and expansion of the protosynapse
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upstream
downstream
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upstream
downstream
Y yeastI invertebrateV vertebrates
Method: Proportion of each functional class with earliest identifiable orthologue
Origins of functional classes
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Evolution of ‘learning molecules’
• neurotransmitter receptors• second messengers• protein synthesis
GO terms
Y yeastW wormF flyZ zebrafishC chickenM mouseH human
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DLG
NRC / MASC
NR
1NR
2
Increased combinations of complexes in vertebratesfrom expansion in paralogues
Invertebrates Vertebrates
Proteins
NR1 1 1NR2 1 4DLG 1 4
Complexes1 16
Theoretically possible MASC combinations in mammals >1030
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Protosynapse‘first synapse’
Synapse evolution
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Protosynapse‘first synapse’ first neurons
Synapse evolution
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Protosynapse‘first synapse’ first neurons
Synapse evolution
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Brain size vs Synapse complexity
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6 myr
75 myr
600 myr
1000 myr
complex s
ynapse
s
big brains
Big synapse proteomes evolved before big brains
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How are complex synapses used in complex brains ?
Examine synapse proteome composition in different in classes of neurons in mouse
Chris Anderson, Cathy Vickers, Andrew Pocklington
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anatomical expression level profiling
>150 MASC/PSD proteins in 22 regions of mouse brain
variation in levels & overlap
Measured:
mRNA
• in situ
• microarray
protein
• immunohistochem
• western
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Combinations of synapse proteome define brain regions, neuron types
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Expression barcode
MASC
0 4 4 3 1
1 4 3 2 3
2 3 2 2 1
anatomicalvariation
phylogeny
recent
ancient
upstream
downstream
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Expression barcode
MASC
0 4 4 3 1
1 4 3 2 3
2 3 2 2 1
anatomicalvariation
phylogeny
recent
ancient
upstream
downstream
Protosynapse has most conserved & uniform expression pattern
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Evolutionary expansions gave combinations used to generate anatomical diversity
Combinations
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Signaling networks in the PSP
a complex combinatorial signalling machine
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NMDA receptor activation with a synaptic plasticity protocol
how many substrates change?
Marcelo Coba, Andrew Pocklington, Mark Collins, Jyoti Choudhary (Science Signalling 2009)
NMDA stimulation (long term depression, LTD)
> 200 phosphorylation sites.> 120 proteins
PSD
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9 of 21 kinases tested
NMDA receptor activation with a synaptic plasticity protocol
how many kinases change?
Marcelo Coba
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Combinatorial outputs
10 phosphorylation sites on 4 proteins
Stimulus:
No change
Increase phos
Decrease phos
Marcelo Coba
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Combinatorial outputs
10 phosphorylation sites on 4 proteins
Stimulus:
No change
Increase phos
Decrease phos
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Combinatorial outputs
10 phosphorylation sites on 4 proteins
Stimulus:
No change
Increase phos
Decrease phos
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Combinatorial outputs
10 phosphorylation sites on 4 proteins
Stimulus:
No change
Increase phos
Decrease phos
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sites states
GluR1 3 8 (23)
10 proteins 100 1030 (2100)
PSP 104 1060
Combinatorial outputs = states
Are any two synapses the same?Can a synapse ever be in the same state twice?What are the physiological constraints?
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kinases
substrates
Postsynaptic kinase-substrate network - mapping 743 phosphorylation events
Marcelo Coba, Andrew Pocklington
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Building the network
defining minimal units
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Number of kinases with n substrates
0
1
2
3
4
5
6
7
8
9
0-5 5-10 10-15 15-20 20-25 25-30 30-35 35-40
n substrate
nu
mb
er o
f ki
nas
es
How many substrates for a kinase?
20.5 ( 8.3) protein substrates phosphorylated by each kinase
k1
PPPkinasedivergence
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Number of sites with n kinases
0
10
20
30
40
50
60
70
80
1 2 3 4 5 6 8 9 10 12
n kinase
num
ber
of
site
s
How many sites were phosphorylated by more than one kinase?
65% (129) sites phosphorylated by multiple kinases
kinaseconvergence
k1 k2 kn
P
• redundance / robustness• multiple upstream receptors
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Hubs – highly connected
SitesProteins
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coincidence detectors
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NMDA receptor
mGluR receptor
Dopaminereceptor
Combinations of sites
Functional orchestration
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EPMBEHAVIOUR
OF NOE FC RR
Synapse evolution and expansion model of synapse diversity and behaviour
-20 0 20 40 60
50
100
150
200
250
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AcknowledgementsProteomicsMarcelo CobaAlex Bayes
Bilal Malik
Mark CollinsJyoti Choudhary
ExpressionChristopher AndersonCathy Vickers
InformaticsAndrew PocklingtonJ. Douglas Armstrong
Mike CroningRichard Emes
Support
Wellcome TrustMedical Research CouncilEuropean Union
www.genes2cognition.orgwww.g2conline.org