Probing molecular mechanisms of neurodegenerative ageing in prion ablated mice
Lead Research Organisation:
The Pirbright Institute
Department Name: Div of TSE
Abstract
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Technical Summary
The transmissible spongiform encephalopathies (TSEs) are associated with accumulation of a protease-resistant and conformationally altered isoform, PrPSc, of the cellular prion protein, PrPC. These diseases are also associated with widespread spongiform degeneration, neuronal loss and astrocytic gliosis and are invariably fatal. It is not clear, however, whether neurodegeneration represents a response to increasing levels of neurtoxic PrPSc (so called gain of function) or is the result of loss of function of endogenous PrPC as it is converted to PrPSc. Mice in which the Prn-p gene has been ablated by gene targeting (PrP0/0) appear largely physiologically normal with no developmental abnormalities, suggesting that loss of function of PrPC may not account for changes seen during TSE disease. However, we have preliminary evidence for significant and dramatic changes in the abundance of certain proteins in the brains of PrP0/0 mice that have been aged to around 825 days, relative to their age-matched wildtype counterparts. These changes appear similar to those seen during TSE-induced neurodegeneration and our data suggest common molecular mechanisms in these two models, indicating that loss of PrPC function may be the pathophysiological event in TSE diseases. Our data suggest that PrPC plays a key role in protection of neurones during the ageing process. We wish to follow up our preliminary micro-array experiments and to extend this study to encompass proteomic and immunohistochemical approaches and propose a concerted programme of work aimed at defining the molecular mechanisms of cerebral dysfunction in PrP0/0 mice. Joint with BB/C506872/1
Organisations
Publications
Banner, S
(2008)
Analysis of murine CNS proteomes from PRP-0/0, PRP-P101LL, PRP-G3 and WT mice
in Joint Funders TSE Workshop
Gill, A
(2008)
Theoretical and mathematical models of prion diseases
in EBRC Launch
Gill, A
(2008)
Molecular dynamics simulations of prion protein variants
in EBRC Launch
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Exploitation Route | Nil return - final report previously submitted |
Sectors | Agriculture Food and Drink Healthcare |
Description | Nil return - final report previously submitted |