Proteolysis: a double-edged sword for the development of amyloidoses

Abstract

The yeast Saccharomyces cerevisiae has proven to be a useful model system to investigate the mechanism of prion generation and inheritance, to which studies in Sup35 made a great contribution. Recent studies demonstrated that 'protein misfolding and aggregation' (i.e. amyloidogenesis) is a common principle underlying the pathogenesis of neurodegenerative diseases including prion, amyotrophic lateral sclerosis (ALS), Perkinson's (PD), Alzheimer's (AD) diseases and polyglutamine (polyQ) diseases such as spinocerebellar ataxia (SCA) and Hantington's disease (HD). By these findings, the yeast has again been drawing increased attention as a useful system for studying neurodegenerative proteinopathies. So far, it has been reported that proteolytic cleavage of causative amyloidogenic proteins might affect the pathogenesis of the respective neurodegenerative diseases. Although those reports provide a clear phenomenological description, in the majority of cases, it has remained elusive if proteolysis is directly involved in the pathogenesis of the diseases. Recently, we have demonstrated in yeast that proteolysis suppresses prion generation. The yeast-based strategy might make a breakthrough to the unsolved issues.

The Role of Proteolysis in Amyloidosis

“…Besides those factors which have been widely recognized to promote amyloid fibril formation, such as genetic mutations, environmental factors, excessive concentration of the precursor protein, chemical modifications [29][30][31][32] or post-translational modifications [33], in vivo fragmentation of the precursor proteins by endogenous proteases is one of the most prominent aspects that characterize amyloid fibrils. On one hand, proteolysis has been implicated in amyloidogenesis in distinct forms of amyloidosis [29,30]; on the other, post-deposition digestion may be implicated in the degradation of pathogenic aggregates [31].…”

“…Besides those factors which have been widely recognized to promote amyloid fibril formation, such as genetic mutations, environmental factors, excessive concentration of the precursor protein, chemical modifications [29][30][31][32] or post-translational modifications [33], in vivo fragmentation of the precursor proteins by endogenous proteases is one of the most prominent aspects that characterize amyloid fibrils. On one hand, proteolysis has been implicated in amyloidogenesis in distinct forms of amyloidosis [29,30]; on the other, post-deposition digestion may be implicated in the degradation of pathogenic aggregates [31]. The aberrant proteolysis of precursor proteins leads to the formation of large fragments which are generally partially unfolded, less stable than the parent proteins, and display a much higher tendency to form self-aggregating folding intermediates, which evolve toward oligomers and, subsequently, amyloid fibers.…”