Explore the prion pathogenic mechanisms by investigating the structure-function relationships of PrP fibrils
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This proposal aims to investigate the pathogenic mechanisms underlying the Creutzfeldt-Jakob disease (CJD). CJD is the prototypical form of a group of cognitive disorders termed rapidly progressive dementias (RPDs), which include the rapidly progressive subtypes of classic dementias such as Alzheimer's disease (AD). Sporadic CJD (sCJD), the most common human prion disease, is characterized clinically by fast cognitive decline with ataxia, myoclonus or other neurological signs, and neuropathologically by the accumulation of misfolded prion protein (PrP), spongiosis, gliosis, and neuronal loss. CJD or prion disease is caused by the pathogenic conversion of the normal cellular PrP (PrPC) to its misfolded and aggregated form, PrPSc or prion. Such autocatalytic PrPSc-templated conversion results in the spreading and accumulation of PrPSc and leads to neurodegeneration. All prion diseases, including CJD, are inevitably fatal, and there are currently no prophylactic or therapeutic remedies available for these devastating disorders. Recent in vitro studies using bacterially expressed recombinant PrP have generated various groups of self-replicating recombinant PrP amyloid fibrils, some of which can induce bona fide prion diseases in animal models. Intriguingly, certain misfolded recombinant PrP fibrils are able to self-propagate in vivo but not cause any disease in animals. Taking advantage of the self- propagating property of the non-pathogenic recombinant PrP fibrils, the current proposal aims 1) to investigate the structural differences between pathogenic and non-pathogenic PrP fibrils by cryo-EM; 2) to investigate the differential glial responses to pathogenic PrPSc and non-pathogenic recPrP fibrils; and 3) to investigate the anti- prion mechanisms of the non-pathogenic recombinant PrP fibrils against prion diseases. These proposed structural and functional studies will contribute to the fundamental understanding of the pathogenic mechanisms of CJD and lay the groundwork for developing novel therapeutic strategies against protein misfolding-associated neurodegenerative diseases.
