Defective Protein Folding and Aggregation as the Basis of Neurodegenerative Diseases: The Darker Aspect of Proteins

Abstract

The ability of a polypeptide to fold into a unique, functional, and three-dimensional structure depends on the intrinsic properties of the amino acid sequence, function of the molecular chaperones, proteins, and enzymes. Every polypeptide has a finite tendency to misfold and this forms the darker side of the protein world. Partially folded and misfolded proteins that escape the cellular quality control mechanism have the high tendency to form inter-molecular hydrogen bonding between the same protein molecules resulting in aggregation. This review summarizes the underlying and universal mechanism of protein folding. It also deals with the factors responsible for protein misfolding and aggregation. This article describes some of the consequences of such behavior particularly in the context of neurodegenerative conformational diseases such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and other non-neurodegenerative conformational diseases such as cancer and cystic fibrosis etc. This will encourage a more proactive approach to the early diagnosis of conformational diseases and nutritional counseling for patients.

Conformational behaviour and aggregation of chickpea cystatin in trifluoroethanol: Effects of epicatechin and tannic acid

“…It exists in competition with the normal folding pathway [1]. It is likely that in many cases when aggregation occurs from a solution of the native protein it is the partially unfolded intermediates in equilibrium with the native state that are the immediate precursors of the aggregates [2].…”

Trifluoroethanol and acetonitrile induced formation of the molten globule states and aggregates of cellulase

“…For example, ␣-to ␤ transitions have been suggested in various conformational diseases, such as Parkinson's, Huntington's or Alzheimer's diseases. Evidences report that aggregates do not develop directly from native conformation but from precursors which are only partially folded [37]. Molten globule states are believed to be similar to partially folded conformation.…”

Aggregation of intrinsically disordered fibrinogen as the influence of backbone conformation

“…The inhibition of protein aggregation is observed in higher concentration of TFE (60 to 70%), due to weakening of the hydrophobic interactions stabilizing the intermolecular β-sheet structure in the protein aggregate. The loss of hydrophobic contacts appears to favor the formation of intramolecular hydrogen bonds over intermolecular hydrogen bonds, leading to formation of helix conformation [28,29].…”