If cellular proteins do not fold into a specific conformation, their function is affected. Ceain disorders arise if specific proteins are misfolded. Which of the following disorders arises due to conformational isomerization?
Human Prion Diseases Prion diseases in human beings are Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSSD) (familial CJD) and fatal familial insomnia (FFI). Cerebral coex becomes sponge-like in CJD. Thalamus is affected in FFI. In Kuru, cerebellum is affected. It is seen in Fore aborigines in Papua New Guinea. The term "Kuru" means "laughing death" in the tribal language. Baruch Blumberg showed that the disease was transmitted by ritual cannibalism (eating of brain of dead person); Carleton Gajdusek isolated the "unconventional virus" from the affected individuals; both of them were awarded Nobel Prize in 1976 PRIONS The central dogma in molecular biology postulated by Watson and Crick in 1953 was that genetic information passes from DNA to RNA and then to protein. In general, this rule still holds good. In 1970, Temin and Baltimore showed that DNA could be synthesized from RNA by reverse transcriptase. This has paly shattered the central dogma. But could proteins act as an information molecule? Could proteins replicate themselves? This question was considered to be heretical till a few years ago, but no longer so. There are a few diseases characterized by very long incubation period of many years. These "slow disease agents" were originally thought to be "unconventional viruses", but now they are proved as prion proteins. Prion Proteins : Abnormal Teiary Structure "Prions" is the acronym for "proteinaceous infective paicles". Stanley Prusiner has described prion proteins (PrP) in 1982, who was awarded Nobel Prize in 1997. PrP is a normal protein of 253 amino acids, found in leukocytes and nerve cells. The matured prion protein (PrP) has 210 amino acids. It exists as asialoglycoprotein, anchored on the cell surface. PrP molecules can undergo a change in structural conformation. The altered molecule is resistant to heat and proteolytic enzymes. The abnormal protein is called PrPsc; "sc" stands for scrapie, the disease in which it was first isolated. Thus, prions are proteins with correct primary structure, but with abnormal teiary structure. The PrP is in alpha-helical form, but PrPSc is in beta-pleated sheets (Fig. 52.9). Protein folding occurs in a stepwise process. As the polypeptide is being synthesized by the ribosome, the initial segment of protein stas to fold. That in turn ors only ceain folding in the next pa of the protein. By this time, hydrophobic regions aggregate into interior of the protein molecule. Chaperons (Chapter 41) also help in the formation of correct folding of proteins. This process is orderly. Minor alterations in the process may alter the teiary structure. Abnormal Proteins can be infectious A normal gene makes the normal PrP protein. Disease is produced when the gene is mutated or if an abnormal PrPsc is injected or ingested. The "Seeding Model" explains that the infectious prion induces the nearby normal protein molecules to unfold to abnormal form. It is similar to the conversion of the good "Dr.Jekyll" to the criminal "Mr. Hyde" (same person with two personalities, described in the famous novel). These abnormal proteins now conve fuher normal proteins into abnormal varieties, producing a "chain reaction" that generates new infectious materials. Pathogenesis of Prion Diseases The lysosomal enzymes could break down the normal PrP; but PrPsc cannot be digested. Hence, the prions are accumulated inside the cells, and eventually the cell dies. One pa of prion protein can cause apoptosis (programmed cell death), which also leads to loss of cells. As a group, they are also called transmissible spongiform encephalopathies (TSF), because the brain becomes riddled with small holes like a sponge. Neurons degenerate, protein deposits may accumulate as plaques and glial cells grow larger. Clinically, rapidly progressive dementia sets in with neurological defects and ataxia. All the prion diseases are slowly progressive, but eventually become fatal.Ref: DM Vasudevan - Textbook of Biochemistry, 6th edition, page no: 588 & 589
Familial fatal insomnia
Hepatitis delta
Pernicious anemia
Lesch-Nyhan syndrome
Metabolism of protein and amino acid