Abstract
Author SummaryIn neurodegenerative diseases, such as Alzheimer's disease and Huntington's disease, specific proteins escape the cell's quality-control system and associate together, forming insoluble aggregates. Until now, little was known about whether proteins aggregate in a non-disease context. In this study, we discovered that the aging process itself, in the absence of disease, leads to the insolubilization and increased aggregation propensity of several hundred proteins in the roundworm Caenorhabditis elegans. These aggregation-prone proteins have distinct structural and functional proprieties. We asked if this inherent age-dependent protein aggregation impacts neurodegenerative diseases. We found that proteins similar to those aggregating in old worms have also been identified as minor components of human disease aggregates. In addition, we showed that higher levels of inherent protein aggregation aggravated toxicity in a C. elegans Huntington's disease model. Inherent protein aggregation is a new biomarker of aging. Understanding how to modulate it will lead to important insights into the mechanisms that underlie aging and protein aggregation diseases.
Highlights
IntroductionThe regulation of protein homeostasis (proteostasis) plays an essential role in preventing protein aggregation
The regulation of protein homeostasis plays an essential role in preventing protein aggregation
Some insoluble protein bands were present at similar levels in young and aged animals, suggesting these include proteins that are not aggregation-prone but rather proteins such as tubulin and cuticular collagen proteins that are functional in an insoluble state
Summary
The regulation of protein homeostasis (proteostasis) plays an essential role in preventing protein aggregation. The tightly regulated balance of gene expression levels, quality control, and protein disposal is disrupted. Aging is associated with increased oxidative stress, leading to irreversible oxidation and nitration of proteins, which impairs their degradation [4,5]. These age-dependent changes in proteostasis are thought to facilitate the aberrant aggregation of specific proteins in the context of neurodegeneration and amyloidoses [6]. It is not clear to what extent this altered cellular environment leads to protein aggregation during normal aging, in a non-disease context [7]
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