[SagarikaGhosh]

It is widely known fact that a large variety of neurodegenerative diseases are caused due to protein misfolding and aggregation as plaques. Diseases like Alzheimer’s , Parkinson’s, Huntington’s, Creutzfeldt- Jacob disease, Gaucher’s disease and even cystic fibrosis are some of the known diseases caused by protein misfolding.

It has been seen that in the majority of protein misfolding disorders, folding is affected due to a mutation causing loss of function, or deleterious gain of function. The former has been observed in cystic fibrosis patients, while the latter is the cause behind Alzheimer’s, Huntington’s etc. Usually molecular chaperones are able to correct the misfolding but in the case of neurodegenerative diseases, molecular chaperones’ functions are blocked and hence natural repair cannot occur. As a result, the misfolded proteins accumulate as fibrous amyloids which when formed in the brain cause lesions.

Research regarding therapeutic mechanism for protein refolding:

Misfolded proteins form a beta sheet structure; hence scientists have been examining the beta folded structure to determine its role in protein misfolding. Beta sheet conformation is formed when protein is oligomerized which can lead to aggregation, loss of biological activity and gain of toxic activity. Scientists have been working on mechanisms to prevent stabilization or oligomerization of the beta sheet. Beta sheet breaker peptides have been used to destabilize the beta sheet’s abnormal structure or to induce its conversion to normal form.

Another mechanism for protein misfolding correction is the use of molecular chaperones. Chemical chaperones have been used to turn back the protein to its natural state. These low molecular mass compounds protect the proteins against denaturation due to heat or chemicals. An example of a chemical chaperone is glycerol which has been used for treatment of cystic fibrosis in case of Delta F08 mutation . Apart from chemical chaperones, pharmacological chaperones have been used for proteopathy studies. Pharmacological chaperones act as ligands which bind to mutant p-glycoprotein that induces aggregation and retention of proteins in the Endoplasmic reticulum. This approach has been tried in case of cancer which is caused by mutations in p53 protein.