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Printable Handouts
Navigable Slide Index
- Introduction
- Overview of the talk
- Overview of neurodegenerative diseases
- Common themes in neurodegeneration
- Synaptic loss and neuronal death
- Protein misfolding and neurodegeneration
- Prion neuropathology findings
- Prion pathological mechanism
- Deck chair analogy - opened
- Deck chair analogy - stacked
- Linking the analogy to the prion mechanism
- Prion pathological mechanism - western blott
- Prion formation and neurotoxicity
- Adult-onset PrPc knockout mouse
- Effect of PrPc depletion in prion-infected mice?
- Effect of PrPc depletion - survival curve
- Early neurodegeneration is reversible
- Learning and memory - object recognition
- Learning and memory - exploration tasks
- Recovery of memory
- Motivational behaviour
- Example of burrowing activity
- Loss of burrowing activity in prion infection
- Summary of knockout model
- Consequences of knockout model study
- How do we understand these pathways?
- Dramatic loss in synaptic proteins at 9 wpi
- Critical decline in synaptic transmission at 9 wpi
- Behavioural change at 9 wpi
- Neuronal loss follows at 10 wpi
- Critical point: reduction in synaptic proteins
- Why sudden drop in protein levels?
- Unfolded protein response (UPR)
- UPR and translation
- Rising levels of misfolded PrP induce eIF2a-P
- Induction of eIf2alpha-P reduce translation
- Protein fraction analysis
- Our hypothesis
- Different modulations of the UPR pathway
- Prion infection and UPR pathway experiment
- eIF2alpha-P levels in the experiment
- Reducing eIF2alpha-P restores global translation
- Reducing eIF2alpha-P restores synaptic proteins
- Reducing eIF2alpha-P restores synaptic function
- Reducing eIF2alpha-P rescues synapse number
- Reducing eIF2alpha-P is neuroprotective
- Reducing eIF2alpha-P increases survival
- Altering the UPR pathway for neuroprotection
- Genetic proof of principle
- Pharmacological proof of principle
- GSK2606414 and the UPR pathway
- GSK2606414 experiment overview
- Erect tail
- Hind limb clasping
- Dragging of hind limbs
- General posture
- Righting relax
- GSK2620414 reverses behavioural deficit
- GSK2620414 reverses memory deficit
- GSK2620414 is neuroprotective
- PrP levels in treated and untreated animals
- Other neurodegenerative diseases
- Further studies (Alzheimer's disease)
- Further studies (PSP and ALS)
- Mechanism of neurotoxicity
- New targets for treatment of neurodegeneration
Topics Covered
- Neurodegenerative diseases and protein misfolding disorders
- Prion disease in mice to study mechanisms of neurodegeneration due to misfolded protein accumulation
- Early prion neurodegenerative change is reversible: access to key neurotoxic pathways
- Critical change is loss of synaptic proteins due to activation of PERK branch of the unfolded protein response
- Modifying this pathway genetically is neuroprotective
- Modifying this pathway pharmacologically is neuroprotective
- Relevance of this pathway in other neurodegenerative diseases with misolded proteins e.g. Alzheimer’s and Parkinson’s and ALS
- Relevance in learning and memory
- Common target for therapy in these disorders
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Mallucci, G. (2014, August 5). Pathogenic mechanisms in prion disease [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 11, 2024, from https://doi.org/10.69645/UQJP6316.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Giovanna Mallucci has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Neuroscience
Transcript
Please wait while the transcript is being prepared...
0:00
So I'm Giovanna Mallucci.
I'm program leader the
MRC Toxicology Unit
and professor of neuroscience.
And I'm also a
consultant neurologist
at the specialist interested dimensions
and Neurodegeneration.
And I'm going to talk to you about
pathogenic mechanisms in prion
disease and also their relevance for
other neurodegenerative diseases,
particularly dementia.
0:22
So in this talk, I'm going to tell
you about the work we've done which
led to the discovery
that early prion
neurodegeneration can be reversed.
I'm going to tell you about
the discovery of the molecules
and pathways that underlie
this process, about
pharmacological treatment
that cures prion disease,
and relevance to other
neurodegenerative disorders.
0:43
So just to introduce the
neurodegeneration diseases
as a group, these include
Alzheimer's, Parkinson's,
Huntington's, ALS, and the rarest
of all are the prion diseases.
The top group-- Alzheimer's,
Parkinson's, and vascular dementia
and other forms of dementia--
threaten to be the second commonest
cause of death in
developed world by 2040.
And this is a massive global crisis
at the moment that led to the G8
summit on dementia, calling for a
cure for these disorders by 2025.
At the moment, they cost
1% of the world's GDP.
So there's a huge economic,
human, and medical burden
on societies of these diseases.
And although prion are the
rarest of these disorders,
they're very important
mechanistically
as they give us insight
into mechanisms.
And the alternate name
for all of those diseases
is the protein misfolding disorders.