All of the following diseases show abnormal folding of proteins except :
Multiple sclerosis[Ref: Harrison 171h/e p. 2647; Harper 27th/e p. 38; Lippincott p. 20j The process of protein folding is remarkably efficient, but sometimes it can go wrong. Incorrectly folded proteins are considered to be the cause of many diseases. Amvloidoses The common characteristic of all amyloidoses is the collection of plaques of insoluble protein in the extracellular tissue which cannot be broken down by enzymes. Their ordered structure gives them a crystal like propeies and they are are made up of long filaments (fibrils) that are formed from densely packed p pleated sheets. There are about 20 different proteins that can act as the building block of these fibrils each of which is associated with a different disease. In the so called systemic amyloidoses, the precursors of these plaques are transpoed through the blood stream from their point of origin to the point of deposition. Localized amyloidoses are of greater clinical significance as they mainly affect the central nervous system, the extracellular tissue of which is paicularly susceptible to damage. Alzheimer's disease One of the main characteristics of Alzhiemer's disease is the accumulation of plaques of insoluble p amyloid in the brain. The p amyloid plaques are formed by cleavage of amyloid precursor protein (APP) by two different enzymatic activities which release amyloid - p peptide fragments that are 40 or 42 amino acids long. These then form fibrils which aggregate into insoluble clumps of p amyloid plaques that surround neurons and cause damage. But this cleavage also occurs in healthy individuals and soluble p amyloid proteins are normal constituents of brain tissue. How, then do the plaques form in Alzhiemer's patients? It is thought that the, mis folding of the protein, dramatically alters its propeies. In the normal protein, hydrophobic amino acids bury themsleves inside the protein right from the sta of the folding. However, if the protein folds wrongly, these hydrophobic amino acids are exposed and they rapidly seek out and bind to hydrophobic groups on other protein molecules forming the insoluble aggregates or plaques that are found in Alzhiemers patients. Prion disease : Prion are fatal neurodegenerative disease caused by transmissible proteins and are characterized by spongiform changes, astrocytic gliomas and neuronal loss from the deposition of insoluble protein aggregates in neural cells. Prions are caused by human prion related protein (PrP) (a glycoprotein rich in a helix). PrP is endogenous to the host and in most people, the PrP protein folds normally leaving the person healthy. Rarely, a mutation in the PrP gene will allow the protein to be made incorrectly and it will fold incorrectly making a PrPsc prion. (Which is a glycoprotein rich in fi sheets). These PrPsc prions when exposed to PrP, which is in the process of folding will encourage that PrP to fold incorrectly too, thus creating another PrPsc. While PrP can be processed and cleaned out of a cell once it has been used, PrPsc is shaped differently enough so that it can't be cleaned out and it aggregates inside the cell. These PrPsc aggregates quickly builds up into plaques destroying the nervous tissue. Thus a pathological prion protein serves as the templates for the conformational transformation of normal PrP into PrPsc. Creutzfeldt Jabok disease is caused by prions. Other examples of disease caused by protein misfolding Huntingtons Parkinson's Amyotrophic lateral sclerosis
Creutzfeldt-jabok disease
Prion disease
Multiple sclerosis
Amylidosis