Dementing diseases are among the most dreaded afflictions from which older people frequently suffer. Alzheimer's disease (AD) is the most common dementia. AD is a neurodegenerative disorder, the etiology of which is unknown expect for some familial cases. Studies on both the familial and sporadic forms of AD have been slow, in part, due to our lack of suitable animal models. In contrast, the availability of animal models for neurodegenerative diseases caused by prions has led to relatively rapid advances. Indeed, prion diseases have become the most will understood CNS degenerative disorders of delayed onset and they are the focus of this proposal. In humans, prion diseases generally occur in older adults but the mechanisms governing their time onset is unknown. Recent studies argue that prion diseases may be disorders of protein conformation. Investigations directed toward elucidating the mechanism of conversion of the cellular prion protein (PrPc) into the scrapie isoform (PrPsc) are proposed. Experimental and theoretical studies on the secondary, tertiary and quartenary structures of PrPc and PrPsc as well as synthetic PrP peptides are planned. To facilitate these investigations, recombinant antibodies to PrPc and PrPsc will be produced which can discriminate between the different conformations of PrP. Studies on the cell-free synthesis of PrP are designed to develop systems for the in vitro generation of PRPSc in conjunction with studies on the renaturation of PrPsc. Besides using conformational dependent PrP antibodies to study PrPsc renaturation and cell-free synthesis, they will be used to investigate the patterns of PrPSc accumulation in sporadic and familial Creutzfeldt-Jakob disease (CJD). Each distinct isolate or """"""""strain"""""""" of scrapie prions has unique pattern of PrPSc accumulation suggesting that the molecular basis of prion diversity resides in the cell-specific synthesis of PrPSc accumulation suggesting that the molecular basis of prion diversity resides in the cell-specific synthesis of PrPSc. The largest focus of familial CJD cause by a PrP codon 200 mutation is found in Libyan Jews living in Israel. Patients as well as at risk and unaffected family members of Libyan Jews will be studied. The investigations proposed here address the molecular mechanism responsible for the pathogenesis of the infectious, genetic and sporadic forms of prion diseases. The diverse skills, talents and background of the investigators in the proposed program offer an unusual opportunity to define the molecular mechanisms responsible for neurodegeneration in prion diseases. Elucidation of the mechanisms by which brain cells cease to function and die in prion diseases after a long delay may offer new approaches to elucidating the etiologies of more prevalent neurodegenerative disorders afflicting older people, including AD.
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