Modifiers of extracellular aggregation in Caenorhabditis elegans

Abstract

Aberrant protein aggregation leads to various age-related disorders. Studies have also shown that several hundred proteins in Caenorhabditis elegans aggregate with age. This suggests that there is an age associated change in the protein homeostasis, which causes proteins to misfold and aggregate. Age-dependent misfolding affects both intracellular proteins and extracellular proteins. The various conditions and factors responsible for maintaining protein homeostasis in the intracellular environment are relatively well understood and protein-quality control in the endoplasmic reticulum has been extensively studied. However, not much is known about protein-quality control outside the cell. A few mammalian extracellular proteins i.e. clusterin, haptoglobin and α2-macroglobulin display chaperone activity by stabilizing secreted misfolded and aggregation-prone proteins such as amyloid-β. Therefore, I speculated that there must be some mechanisms that regulate extracellular protein aggregation in C. elegans.

In this study, I used C. elegans as a model to investigate the age dependent aggregation of the extracellular protein LBP-2. I found out that the rate of extracellular accumulation is significantly slower in the daf-2 mutants and by suppression of insulin/IGF-1 signalling by RNAi. I also found that higher temperature leads to increased amount of extracellular aggregation in the worms. In this study, I also carried out an RNAi screen to look for factors that can modify extracellular aggregation. I found 14 such potential candidate factors. Additionally, I found that these candidates do not have any significant influence on the lifespan of the organism. But, these candidates do play an important role in the worm’s ability to resist heat stress.