PRIONS 221

PRIONS Infectious agent made of proteins WHICH ARE NOT ASSOCIATED WITH A NUCLEIC ACID Infect by folding and unfolding into irregular conformations The abnormally folded molecule is able to convert proteins into correctly folded form This process perpetuates the infection

PRION DISEASES GENETIC COMPONENT INFECTIVE PARTICLE BOVINE SPONGIFORM ENCEPAHLOPATHY

HUMAN PRION DISEASES CREUTZFELD-JACOB DISEASE( 1 PER MILLION PEOPLE PER YEAR) FATAL FAMILIAL INSOMNIA KURU ALPERS SYBNDROME

MECHANISM All known prions are believed to infect and propagate by formation of an AMYLOID fold, in which the protein polymerizes into a fiber with a core consisting of tightly packed BETA SHEETS. Other mechanisms may exist in yet undiscovered infectious protein particles.

KURU – NEW GUINEA

CANNIBALISM

BSE Bovine Spongiform Encephalopathy (BSE), also known as "Mad Cow disease," has emerged as one of the most serious health concerns of the 21st century. No one knows for certain what causes BSE or its human equivalent, Creutzfeldt Jakob disease (CJD). However, a majority of scientists suspect the culprit may be an aberrant protein known as a prion found in the brains and spinal tissue of infected animals. Experts also believe outbreaks of BSE in European cattle stem from the once common practice of feeding these animals OFFAL

AMYLOID PLAQUES IN NERVOUS TISSUE

Holes produced by the prions

Prions - Genetics The prion is a product of a human gene, termed the PrP gene, found on chromosome 20. This gene contains two exons separated by a single intron. Exon I and Exon II are transcribed and the two RNAs ligated into a single mRNA. This mRNA contains an open reading frame (ORF) or protein coding region which is translated into the PrP protein. The PrP protein is a precursor of the prion protein. It is termed PrP 33-35.  

The PrP 33-35 undergoes several post-translational events to become the prion protein (PrP 27-30): 1.  Glycosylation - at two sites. 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.  

Humans and infections Acquired infections Diet Surgery Corneal transplants

Hereditary factors A strain of mice that has a predisposition to prion related diseases Sporadic Appears to be a dominant pattern

Prion Genotypes Genetic predisposition for Scrapie in sheep Scrapie susceptible sequences have been located in sheep in New Zealand and Australia

Scrapie

FATAL FAMILIAL INSOMNIA; FFI( OMIM) - Although the thalamus is affected in diffuse degenerative processes of the nervous system, a genetically determined degenerative disease limited to selected thalamic nuclei seems to have been described first by Lugaresi et al. (1986). They reported the case of a 53-year-old man who presented with progressive insomnia and dysautonomia (pyrexia, diaphoresis, myosis, and sphincter disturbances). Dreamlike status, dysarthria, tremor, and myoclonus subsequently developed and led to coma and death after 9 months. Two sisters of the patient and many relatives over 3 generations had died of a similar disease. Pathologic studies of the brains of the patient and 1 of his sisters showed severe neuronal degeneration, with reactive astrocytosis limited to the anterior and dorsomedial thalamic nuclei and without spongiosis or vascular or inflammatory changes.

Mice – Experimental evidence Mice inoculated with brain homogenates from subjects with fatal familial insomnia or sporadic fatal insomnia had lesions of similar types and distributions in their brains. In both familial and sporadic fatal insomnia, the molecular mass of the Prp(Sc) fragment was 19 kD in these mice. In contrast, these characteristics were different in the mice inoculated with homogenate from patients with typical sporadic or familial Creutzfeldt-Jakob disease, and the molecular mass of their PrP(Sc) was 21 kD.