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NextLecture2. To introduce the concept of the "prion" as an etiological agent of human disease.
3. To introduce the concept of the "viroid" as a disease entity.
4. To familiarize you with the current concepts of the structure, replication and pathogenicity of the prion and viroid.
The PrP 33-35 undergoes several post-translational events to become the prion protein (PrP 27-30):
2. Formation of a disulfide bond between two cysteine residues.
3. Removal of the N-terminal signal peptide.
4. Removal of the C-terminal hydrophobic segment.
5. Addition of a phosphatidylinositol glycolipid at the C-terminal.
6. Removal of the N-terminal first 57 amino acids.
2. The -sheet-forming peptides aggregate to form amyloid fibrils.
3. The amyloid fibrils kill thalamus neurons through apoptosis, a programmed series of events that leads to cell death.
2. Depletion of dendritic spines in neurons.
3. Formation of numerous vacuoles in the cerebellar cortex (spongiform encephalopathy).
4. Amyloidosis - deposition of amyloid in the cerebellar cortex, thalamus, brain stem and in the lumen of blood vessels within the brain. These amyloid plaques consist of discrete eosinophilic glassy-appearing masses, often having radiating amyloid fibrils at their periphery. The plaques are primarily subependymal, subpial and perivascular.
These pathologies give rise to the clinical symptomology seen in these patients. These are:
1. A long incubation period (several years) which has given rise to the term "slow infection."
2. Loss of muscle coordination which leads to a difficulty in walking, indicating a functional disorder of the cerebellum.
3. Dementia characterized initially by loss of memory, diminished intellect and poor judgement.
4. Progressive insomnia characterized by a marked reduction or loss of the slow-wave and rapid-eye-movement phases. D. Transmission
Spread of the disease is via horizontal transmission, i.e., transmission from one person to another, either directly or by fomites.
Because of their simplified structures both prions and viroids are sometimes called subviral particles. Viroids mainly cause plant diseases but have recently been reported to cause a human disease.
Catalytic RNAs are those that have the intrinsic ability to break and form covalent bonds; Viroids are catalytic RNA's (ribozymes) that cleave RNA to produce fragments containing a 5'-hydroxyl and a 2', 3'-cyclic phosphate.
This is a nonhydrolytic reaction in which the same number of phosphodiester bonds are maintained and the transesterification reaction is theoretically reversible. This reaction is considered to play an essential role in the replication of these RNAs in vivo. Such reactions are all intramolecular and hence quasi-catalytic with single turnover. These RNAs can be manipulated, however, to provide true catalytic cleavage in trans-reactions.
In the first variation (A), the circular plus strand is copied by viroid RNA-dependent RNA polymerase to form a concatameric minus strand (step 2). Site-specific cleavage (arrows) of this strand produces a monomer that is circularized by a host RNA ligase (step 3) and then copied by the RNA polymerase to produce a concatameric plus strand. Cleavage of this strand (step 5) produces monomers which, on circularization, produces the progeny circular, plus RNA, the dominant form in vivo.
In the other variation (B), the concatameric minus strand of step 1 is not cleaved but is copied directly to give a concatameric plus strand (step 3), which is cleared specifically to monomers for ligation to the circular progeny. Those RNAs that self-cleave only in the plus strand in vitro are considered to follow this route.
Medori, R., et al., 1992. Fatal Familial Insomnia, A Prion Disease with a Mutation at Codon 178 of the Prion Protein Gene. The New England Journal of Medicine 326:444-449.
Taylor, J.M., 1992. The Structure and Replication of Hepatitis Delta Virus. Annual Reviews of Microbiology 46:253-276.
Touchette, N., 1993. ß-sheet structure is key issue in prion disease. The Journal of NIH Research 5:57-59.
Barinaga, M., 1993. Ribozymes: killing the messenger. Science 263:1512-1514.
Prusiner, S.B., 1995. The Prion Diseases. Scientific American 272: 48-57.
2. Prions are infectious agents composed solely of glycoprotein. They are products of a human gene which accumulate in tissue as amyloid.
3. Amyloid deposition in tissue is a pathological manifestation of many diseases, of both prion and non-prion etiology. These diseases include Alzheimer's disease, *Creutzfeldt-Jakob disease, Down's syndrome (mongolism), *fatal familial insomnia, *Gerstmann-Straussler syndrome, *kuru and leprosy. (* indicates prion diseases).
4. The accumulation of amyloid induces these pathologies in the host: astrocyte gliosis, depletion of neuronal dendritic spines, spongiform encephalopathy.
5. In prion disease there is a long incubation period before one sees loss of muscle coordination, dementia and/or progressive insomnia.
6. Prions induce no immune reactions within the human.
7. Viroids are infectious agents composed solely of circular single-stranded RNA which folds over on itself to form some double stranded regions. These are catalytic RNAs (ribozymes).
8. The only human disease known to be caused by a viroid is hepatitis D; in this case the viroid is enclosed in a hepatitis B virus capsule.
9. The hepatitis D viroid manifests its disease potential by sequestering and/or destroying human liver 7S RNA.
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