pathogenic mechanisms in prion disease prof. giovanna …prof. giovanna mallucci the screen versions...
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Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Prof. Giovanna Mallucci
MRC Toxicology Unit
University of Leicester
Pathogenic Mechanisms in Prion Disease
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1. Discovery that early prion neurodegeneration can be reversed
2. Discovery of the molecules and pathways underlying this
3. Pharmacological treatment that cures prion disease
4. Relevance to other neurodegenerative disorders
Overview
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Neurodegenerative diseases
• Alzheimer’s
• Parkinson’s
• Huntington’s
• ALS
• Prion
WHO: by 2040 second commonest cause of death in developed world
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Common themes in neurodegeneration
• Aggregation of misfolded proteins
• Early synaptic dysfunction and loss
• Irreversible neuronal loss
• Common pathways?
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Misfolded protein
accumulationSynapse
number
Symptoms Neuronal death
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How do we understand how protein misfolding
causes neurodegeneration?
Prion disease
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Prion neuropathology
PrP amyloid deposits PrPSc’
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Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Prion formation and neurotoxicity
Toxic intermediate?
Aggregate toxicity?
Oligomeric form?
recruitment
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Adult-onset PrPC knockout mouse
Mallucci et al., EMBOJ 2002
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What is effect of PrPC depletion
in prion-infected mice?
CNS prion infection
established
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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16 Mallucci et al., Science 2003
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Early neurodegeneration is reversible
Progressive neurotoxicity Reversal of neurotoxicity
Mallucci et al., Science 2003
Mallucci et al., Neuron 2007
White et al., PNAS 2008
8 wpi
control 12 wpi
control
12 wpi
knockout
8 wpi
knockout
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Learning and memory
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Recovery of memory
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Motivational behaviour
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Displacement of food pellets from a tube of given size within 24 h
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Loss of burrowing activity in early prion infection
Controls
Mallucci et al., Neuron 2007
Controls
PrP deleted
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Early neurodegeneration is reversible
Progressive neurotoxicity Reversal of neurotoxicity
Mallucci et al., Science 2003
Mallucci et al., Neuron 2007
White et al., PNAS 2008
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Early deficits are reversible – result in long
term neuroprotection
Early deficits are reversible – result in long
term neuroprotection
Access to key neurotoxic –
and neuroprotective - pathways
Window for interventionWindow for intervention
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How do we understand these pathways?
Mallucci et al., Science 2003
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Dramatic loss in synaptic proteins at 9 wpi
Moreno et al., Nature 2012
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Critical decline in synaptic transmission at 9 wpi
Moreno et al., Nature 2012
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Behavioural change at 9 wpi
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Neuronal loss follows at 10 wpi
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Critical point: reduction in synaptic proteins
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Why sudden drop in protein levels?
• Increased breakdown?
• Decreased synthesis?
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Unfolded protein response (UPR)
Caspase
cleavage
Reduced translation
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Restored translationReduced translation
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Rising levels of misfolded PrP induce eIf2αααα-P
Moreno et al., Nature 2012
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Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Sustained activation: Neurodegeneration
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Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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40 Moreno et al., Nature 2012
Prion Treatment
Prion +Salubrinal
Prion +LV-shPrP
Prion +LV-GADD34
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Prion +Salubrinal
Prion +LV-shPrP
Prion +LV-GADD34
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Reducing eIF2αααα-P restores global translation
Moreno et al., Nature 2012
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Reducing eIF2αααα-P restores synaptic proteins
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Reducing eIF2αααα-P restores synaptic function
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Reducing eIF2αααα-P rescues synapse number
Moreno et al., Nature 2012
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Reducing eIF2αααα-P is neuroprotective
Moreno et al., Nature 2012
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Reducing eIF2αααα-P increases survival
Moreno et al., Nature 2012
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Reduced translation
Synaptic failure
Neurodegeneration
Neuroprotection
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Genetic proof of principle
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Pharmacological proof of principle
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Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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52 Moreno et al., Sci. Trans. Med. 2013
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Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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GSK2620414 reverses behavioural deficit
Moreno et al., Sci Trans Med 2013
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GSK2620414 reverses memory deficit
Moreno et al., Sci Trans Med 2013
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GSK2620414 is neuroprotective
Moreno et al., Sci Trans Med 2013
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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PrP levels are the same in treated
and untreated animals
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Other neurodegenerative diseases
• Common pathways: PERK/eIF2a-P elevated in
– Alzheimer’s
– Parkinson’s
– ALS
– Human prion disease brains
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Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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naturenaturenaturenaturegeneticsgeneticsgeneticsgenetics
6564 8 10 12
wpi
Synapse
number
Misfolded proteins:
Aβ, tau, α-syn,
prion…
Mechanism of neurotoxicity
in protein misfolding disorders
impaired translation
UPR activation
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Reduced translation
Synaptic failure
Neurodegeneration
New targets for treatment of neurodegeneration
Neuroprotection
Pathogenic Mechanisms in Prion Disease
Prof. Giovanna Mallucci
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