Protein Misfolding and Propagation in Neurodegenerative Diseases

Protein misfolding is the hallmark of a large number of neurodegenerative diseases and is characterized by the presence of amyloid inclusions composed of aggregates of misfolded proteins in specific areas of the brain. The formation of those aggregates involves a multistep process that is exacerbated during periods of cellular stress. Cells have several mechanisms to regulate protein quality control that also serve as a defense line to prevent the accumulation of misfolded proteins; failures in these defenses are frequently involved in neurodegeneration. Another intriguing feature of neurodegenerative diseases, which have misfolded proteins as etiological agents, is the presence of similarities with prion diseases. Prions are unconventional infectious agents composed entirely from a misfolded form of a native protein that has the capacity to provoke and propagate to neighboring cells or even to other organisms. Nowadays, a large body of evidence has shown that most of the misfolded proteins found in degenerated brains behave as prion-like proteins, promoting misfolding and consequently, the aggregation of native protein forms which can spread to other cells or brain regions. However, unlike prion diseases, the prion-like properties of misfolded proteins are unable to naturally infect other organisms. Taken together, neurodegenerative diseases share many characteristics, of which protein misfolding is the most important. This feature has huge therapeutic implications since it raises the possibility to treat different diseases with drugs targeted to impair, block or revert protein misfolding.

Keywords: Protein aggregates, oligomers, fibrils, amyloid plaques, tangles, Lewy bodies, chaperones, protein degradation, oxidative damage.