Objective
Neuronal loss is one of the main pathological features of the Transmissible Spongiform Encephalopathies (TSEs or "prion diseases"). Other pathological changes include accumulation of protease-resistant isoforms of the prion protein PrP (PrPsc), vacuolation of neuronal processes and activation of astrocytes and microglia in affected areas of the brain. The neuronal loss occurs by apoptosis, although mechanisms inducing this neuronal death are not understood. The aims of this proposal are to use a PrP-glia-neuron culture system to investigate factors inducing PrP-stimulated neuronal apoptosis and to screen the ability of selected compounds to reduce/abolish PrP-induced neurotoxicity.
Various in-vitro studies have shown that PrPsc and a PrP peptide (human PrP106-126) are neurotoxic and also stimulate glial proliferation, and that microglia stimulated by PrP106-126 produce neurotoxic products.
This suggests that PrP-induced neuronal toxicity occurs by direct and indirect mechanisms. Thus, testing the ability of compounds to abrogate this toxicity must examine both these possibilities. In addition, the effects of known PrP-associated proteins in modulating neurotoxicity and the effects of such compounds will be examined.
We therefore propose to investigate the following hypotheses:
1. Forms of PrP that contain ß sheets cause activation of both astrocytes and microglia and are neurotoxic.
2. Glia activated by these forms of PrP produce neurotoxic substances
3. PrP-associated macromolecules modulate these responses.
4. Potential therapeutic agents abrogate these effects.
These hypotheses will be approached with in-vitro experiments by exposing primary cultures of CNS cells to prpSC and PrP-based peptides with known structural properties. Attention will be focused on
[i] the effects that direct exposure to PrP preparations have on the survival/death of neurons and
[ii] effects that glia, previously exposed to PrP preparations, have on neuronal cultures. For these experiments, primary cultures of neurons, mixed astrocyte/microglial cultures and cultures enriched for astrocytes or microglia will be generated from embryonic or newborn mice. Peptides based on the mouse prn-p a sequence with defined potential to aggregate and form fibrils will be chosen and used to investigate whether the structural state of the protein is critical in its pathological effects.
These PrP preparations will also be pre- incubated with proteins known to co-localise with PrP in-vivo to determine the effects that such extracellular chaperone-like macromolecules have on the biological properties of PrP. Selected pharmacological agents will be tested for their ability to abrogate direct/indirect PrP-induced neurotoxicity. To date, such approaches to define the direct effects of amyloidogenic PrP protein on cells have provided conflicting data. We seek to resolve these anomalies by conducting an integrated, five-centre research programme and using standardised protocols.
The combination of the different expertises of the partners long-standing experience in the field of scrapie related diseases and disease models, cell culturing, mRNA and protein expression level estimations, production of purified forms of the infectious prpSC agent, peptide production and physical characterization, binding of chaperones to amyloidogenic proteins/peptides represent necessary elements to acquire a fundamental insight in the basic mechanisms of the pathology of prion disease. The knowledge obtained about the type(s) of mediator molecules involved may indicate possible treatments of the TSEs; appropriate drugs will be screened using this in-vitro model.
Such knowledge could also strengthen our understanding of neurodegeneration in other conditions such as Alzheimer's disease where ß-sheet forms of an amyloid protein and glial activation are associated with disease pathogenesis.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- medical and health sciences basic medicine neurology dementia alzheimer
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences basic medicine pathology
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Coordinator
G61 1QH GLASGOW
United Kingdom
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