Evidence for synaptic dysfunction in Prion disease
Evidence for synaptic dysfunction in Prion disease
Recent evidence indicates that neuronal degeneration begins at the level of the synapse and progresses via a retrograde mechanism towards the cell body. Synaptic loss, indicated by a reduction in synaptic protein staining, occurs relatively early in the disease time course and correlates with behavioural abnormalities that are indicative of hippocampal dysfunction. The molecular mechanisms underlying synaptic dysfunction are currently unresolved.
In this current study, we have used the murine scrapie agent, ME7, to model the pathogenesis of prion disease, focussing upon hippocampal synapses. We hypothesised that synaptic dysfunction accounted for early behavioural changes, and that alterations in synaptic function were related to abnormalities in synaptic ultra-structure at the protein level. We have investigated the relationship between synaptic structure and synaptic dysfunction using qualitative and quantitative biochemical and morphological techniques.
We have documented a selective disease-specific loss of pre-synaptic terminals prior to overt alterations in post-synaptic terminals, which is significant at 12 weeks and 21 weeks post-infection. Significant enlargement of the remaining functional synapses is interpreted as a compensatory mechanism for the loss of adjacent synapses. Within the synaptic terminal, a significant reduction in vesicle proteins and associated co-chaperone proteins implies that disease-specific protein dysfunction is targeted to a specific subset of synaptic proteins. These changes in protein expression are detectable at the same time in the disease speculate period that behavioural abnormalities are reported to occur. We therefore speculate that alterations in vesicle trafficking and chaperoning neuroprotective mechanisms initiate early synaptic dysfunction which subsequently manifests itself as subtle behavioural abnormalities relating to hippocampal dysfunction.
University of Southampton
2006
Gray, Bryony Catherine
(2006)
Evidence for synaptic dysfunction in Prion disease.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Recent evidence indicates that neuronal degeneration begins at the level of the synapse and progresses via a retrograde mechanism towards the cell body. Synaptic loss, indicated by a reduction in synaptic protein staining, occurs relatively early in the disease time course and correlates with behavioural abnormalities that are indicative of hippocampal dysfunction. The molecular mechanisms underlying synaptic dysfunction are currently unresolved.
In this current study, we have used the murine scrapie agent, ME7, to model the pathogenesis of prion disease, focussing upon hippocampal synapses. We hypothesised that synaptic dysfunction accounted for early behavioural changes, and that alterations in synaptic function were related to abnormalities in synaptic ultra-structure at the protein level. We have investigated the relationship between synaptic structure and synaptic dysfunction using qualitative and quantitative biochemical and morphological techniques.
We have documented a selective disease-specific loss of pre-synaptic terminals prior to overt alterations in post-synaptic terminals, which is significant at 12 weeks and 21 weeks post-infection. Significant enlargement of the remaining functional synapses is interpreted as a compensatory mechanism for the loss of adjacent synapses. Within the synaptic terminal, a significant reduction in vesicle proteins and associated co-chaperone proteins implies that disease-specific protein dysfunction is targeted to a specific subset of synaptic proteins. These changes in protein expression are detectable at the same time in the disease speculate period that behavioural abnormalities are reported to occur. We therefore speculate that alterations in vesicle trafficking and chaperoning neuroprotective mechanisms initiate early synaptic dysfunction which subsequently manifests itself as subtle behavioural abnormalities relating to hippocampal dysfunction.
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Published date: 2006
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Local EPrints ID: 465922
URI: http://eprints.soton.ac.uk/id/eprint/465922
PURE UUID: 0374c09c-fcb1-42e2-9fcf-98019508f362
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Date deposited: 05 Jul 2022 03:35
Last modified: 05 Jul 2022 03:35
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Author:
Bryony Catherine Gray
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