Prion

 

                                                        Prion

                                P.K.Ghatak,MD

Dr. Daniel Carleton Gajdusek in 1957, while studying a spongiform encephalitis called Kuru, in the local population of Papua New Guinea who were cannibals, proved that Kuru was an infectious disease when he successfully reproduced the disease by injecting the brain extract of Kuru victims in chimpanzees. He theorized Kuru was due to a slow growing unknown virus. It became evident that it was not a virus because Ultraviolet radiation did not kill the infective agent, on the other hand, was sterilized by a protein alerting chemical, bleach.

 In 1982, Stanley Prusiner of UC at SF called the infective agent "a proteinaceous particle and named it  Prion.

Prion is simply a protein molecule made up of 259 amino acids. All living animals and plants, including yeast, have prions in the cell membrane and in the cytoplasm. Neurons have the highest concentration of normal Prion molecules.

Chemical compounds like toxins, snake poison, etc., are also compounds of proteins but Prions differ from toxins in that Prions multiply in huge numbers in the victim's body, whereas, poison and toxins do not. The Medical community was naturally skeptical that an inert protein molecule could multiply in a victim without having Nucleic acids or DNA or RNA.

Dr. Prusiner proved that the infectious Prion (PrP sc), once introduced into the living cells it induces a change of configuration of normal similar protein molecules to adopt the shape and appearance of the PrPsc. The newly formed PrPsc, in turn, makes changes to more protein molecules and the chain reaction follows.

Normal protein molecule is alpha helical in their molecular foldings but abnormal Prion takes beta helical foldings. Misfolded protein molecules prevent cells from carrying out normal cell functions, including elimination of metabolic wastes. Accumulated wastes clog the cells to death. The brain cells (neurons) have a high concentration of Prion molecules. As the misfolded cells die, they leave behind many small voids in the brain matter. Loss of vital functions of the brain cells results in progressive dementia, a movement disorder, and other symptoms, leading to premature end of life. The pathological process is called spongiform encephalopathy because of the resemblance with a sponge.

In the normal individual, the nature has provided a gene called the PRNP gene, that regulates the rate of conversion of misfolded proteins. When a mutation occurs in the PRNP gene, the mutation is passed to the next generation by an Autosomal Dominant fashion. Normal prion protein PRNP codon 129 also exists in polymorphic forms in association with variants Type 1 and Type 2 genes, which arise out of coding errors for amino acid methionine and valine respectively. The combination of these mutations results in 6 subtypes. This explains the variable penetration and low frequency of disease despite dominant inheritance.

Daniel Carleton Gajdusek and Stanley Prusiner received the Nobel Prize in medicine in 1976 and 1999 respectively.

These are the notations used when referring to a particular Prion and a prion disease.

Normal- PrP.  Scrapi - PrPsc.  Creutzfeldt-Jackob disease - CJD.  Variant CJD - vCJD, Familial - f CJD, Spontaneous -sp CJD.

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Diseases caused by prions in humans are

CJD Creutzfeldt-Jacob Disease.

vCJD (variant CJD).

Kuru.

Gerstmann Straussler -Scheinker syndrome (GSSS),

Fatal Familial insomnia,

In mammals prion causes Scrapie in sheep,

Mad-cow-disease in cattle.

Chronic wasting disease in deer, elk, moose, reindeer and caribou.

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