1Prions and prion diseases- prions are novel transmissible pathogens causing a group ofinvariably fatal neurodegenerative diseases- can present as genetic, infectious, or sporadic disorders- all are believed to involve modifications of the prion protein, PrP- prion: proteinaceous infectious- incidence of all human prion diseases: 1 in 1,000,000Prion diseaseshuman: Creutzfeldt-Jakob disease (CJD)Gerstmann-Straussler-Scheinker disease (GSS)fatal familial insomnia (FFI)fatal sporadic insomnia (FSI)kuruanimals: scrapie (goats and sheep) bovine spongiform encephalopathy (BSE or MadCow) chronic wasting disease (deer and elk)TSE: transmissible spongiform encephalopathy2Historical background- in 1920s, Creutzfeldt and Jakob described first cases of progressive mental, motor and neurological deficits in young patients - the eponym 'Creutzfeldt-Jakob disease’ (CJD) was first used to describe degenerative CNS diseases- in 1950s, disease known as 'kuru', in Papua New Guinea discovered; neuropathological similarity between kuru, CJD, and scrapie noted- in 1960s, the term transmissible spongiform encephalopathy (TSE) applied after discovery of the transmissible ability of both kuru and CJD diseases to chimpanzees- in 1976, Gajdusek awarded Nobel prize for his work on 'slow virus' infections theory- in 1980s, the 'protein-only' hypothesis was developed by Prusiner; he was awarded Nobel Prize in Medicine in 1997 for his work on prions; theory remains controversial- in 1990s, outbreak of BSE in cattle in UK raised public concern and spawned vigorousresearch efforts to understand mechanism underlying prion diseasesacquired prion diseases in humans include iatrogenic (iCJD) and kuru- iCJD arises from accidental exposure to human prions throughmedical or surgical- kuru arises from participation in cannibalistic feastsin the late 1950s, an epidemic arose amongst the Fore linguistic group and neighbouring tribes in the Eastern Highlands of Papua New Guinea - investigators realized that kuru was transmitted by the cannibalistic ritual of eating the brains of dead relatives epidemic was thought to have originated due to a case of sporadic CJD; this person was subsequently eaten and passed along the prions to relatives(a switch from sporadic to acquired)3- sporadic CJD (sCJD) occurs in all countries with a random case distribution- about 15% of human prion diseases are inherited; all involve codingmutations in the prion protein gene (PRNP) and have an autosomal dominantinheritance pattern (the formation of PrPSc represents a gain of dysfunction)discovery of inherited prion disorders lends support to prion hypothesis andbroaden the clinical spectrum of these diseases to include atypical dementiaand fatal insomnias* no pathogenic mutations in PrP are found in sporadic or acquired priondiseases- a common PrP polymorphism at residue 129 is a key determinant of geneticsusceptibility to acquired and sporadic prion diseases- variant CJD (vCJD) appeared in the UK in 1995 and found to be causedby the same prion strain that causes BSE in cattle* raised the possibility that a major epidemic of vCJD would occur in the UKas a result of dietary exposure to BSE prionsthe patient was an avid eater of meat pies which were made of predominantlyanimal by-products such as organs (these tissues can contain high amountsof prions)4Incidence of MadCow diseasein the UKIncidence of Kuru in PapuaNew Guinea* the spread of MadCow was contained by the systematic slaughter of suspectedcattle* the incidence of kuru was decreased after missionaries in the region convincedthe affected communities to stop their cannibalistic ritual Clinical features of prion diseases- all the disorders are associated with variable dementia due to loss of specific neurons in the brain (large vacuoles can form in neurons that may fuse to create a spongiform change, hence the term spongiform encephalopathies)-diseases are characterized by loss of motor control, progressive dementia, paralysis and wasting; in the terminal stage, patient is usually mute, rigid and unresponsive (akinetic mutism) - CJD has cerebral involvement so dementia is more common; patient seldom survives a year- GSS is distinct from CJD characterized by cerebellar ataxia and concomitant motor problems, dementia is less common (disease course lasts several years before ultimate death)- fatal insomnias present with an untreatable insomnia and dysautonomia; pathological changes are characterized by severe selective atrophy of the thalamusprognosis: death within one year after the onset of symptoms in 90% (further 5% of patients die within the next year5Potential mechanism of neuroinvasion of prionsPrions: a new form of biological information- the infectivity of prions is believed to occur solely through the uniqueconformation of the prion protein (PrPSc); this infectivity is inactivated byagents that denature or hydrolyze proteins such as high concentrations oftrypsin or SDS- procedures that alter nucleic acids such as UV irradiation do not affectinfectivity- in contrast to viruses with a nucleic acid genome that encode informationin genes, prions encipher infective properties in the tertiary structure of PrPSc- PrPSc acts as a template upon which normal PrP is refolded into a nascentPrPSc molecule with the assistance of another protein6general features of prion proteins- resistance to protease treatment (proteinase K)- insensitive to irradiation such as UV 254nm (suggests thatnucleic acids are not present)- forms aggregates or prion rodshow are prions different from viruses?- prions can exist in multiple molecular forms whereas viruses exist in a single form with a distinct ultrastructural morphology (prion infectivitydetected in prion particles with a wide range of sizes)- prions are nonimmunogenic because the normal proteinPrPC rendersthe host tolerant to PrPSc , viral proteins are seen as “foreign” and almostalways elicit an immune responseStructure of the PrP protein7properties of PrP isoforms- normal form of the protein, PrPC, is a 35kDa cell surface glycoproteinthat is anchored to specific areas of the membrane (caveolae or lipid rafts)by a glycosyl phosphatidyl inositol (GPI) lipid linker - it may have a role incell adhesion or signaling processes- half-life on the cell surface is 5 h, after which protein is internalized bya caveolae-dependent mechanism (conversion to PrPSc likely occurs duringthis internalization)- the acidic pH of the endosomal compartment may