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Understanding the regulation of physiological protein aggregation with age

Final Report Summary - AGGREGATINGPROTEOME (Understanding the regulation of physiological protein aggregation with age)

Aging is a major risk factor for neurodegeneration, cancer, heart disease and confers susceptibility to infections. Using the model organism Caenorhabditis elegans, we have shown that aging is associated with the increased insolubility and aggregation of several hundred “normal” proteins in the absence of disease (David et al. 2010, PLoS Biology). Until recently, it was widely assumed that protein aggregation is mainly restricted to the extensive aggregation of a few hallmark proteins in the context of diseases such as Alzheimer’s, Parkinson’s and systemic amyloidosis. Disease protein aggregation is characterized by the change in conformation and tight self-association of specific proteins to form highly insoluble clumps. Our work shows that protein aggregation is a more widespread phenomenon, which is also relevant in the absence of disease. One major question is what goes wrong during aging to cause this widespread inherent protein aggregation. Intracellular protein-quality-control systems play an important role in preventing disease-related protein aggregation, but it remains unclear how they deal with inherent protein aggregation during aging.

The first objective of this project was to determine how the intracellular quality-control systems regulate inherent protein aggregation. We have developed a system to examine the dynamics of protein aggregation with age. We have made significant steps towards understanding how the degradation systems modulate inherent protein aggregation in different tissues. Moreover we have performed a study investigating how long-lived C. elegans, which up-regulate the protein-quality-control systems, control inherent protein aggregation. Using proteomics, we evaluated changes in protein insolubility between control and long-lived C. elegans with reduced insulin/IGF-1 signaling. We showed that a wide variety of RNA granule components, including stress granule proteins, become highly insoluble with age. Importantly, stress-granule-related RBP aggregates are associated with decreased fitness. We revealed that the activation of both transcription factors HSF-1 and DAF-16 efficiently prevent stress-granule-related RBP aggregation in long-lived animals. This work was published in Cell Reports in January 2017.

The second objective was to discover new factors that regulate extracellular protein aggregation in C. elegans. Indeed, unlike intracellular protein-quality-control, little is known about the corresponding systems in the extracellular space. We have performed a RNA interference screen and identified several regulators of extracellular protein aggregation. We are currently studying the mechanisms involved.

Overall, understanding the mechanisms behind inherent protein aggregation will give us fundamental insight into the process of aging. These results will be especially relevant in the context of neurodegeneration, as we have found multiple interactions between the processes of inherent protein aggregation with age and disease-related aggregation and pathology.