PROTEOSTASIS

Cell-type-specific modulation of protein homeostasis in health and disease

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 Obiettivo del progetto (Objective)

'The correct folding and assembly of proteins and protein complexes is essential to cellular function. Cells have evolved a network of proteins that detect and correct protein damage to maintain proteome health. However, many protein-misfolding diseases, including Huntington’s and Alzheimer’s diseases, are characterized by the accumulation of damaged proteins with devastating consequences for protein homeostasis (proteostasis), resulting in a collection of deleterious phenotypes and affecting many processes. Given that protein expression is cell-type specific, the proteins affected across different cell types are expected to vary. If this is in fact true, then the protein expression profile of a cell will have a profound impact on the folding capacity of its proteins in health and disease. The objective of this project is to determine how cellular proteostasis is adjusted in a cell-specific manner. To this end, I will combine several complementary approaches to compare proteostasis network interactions in different cell types of Caenorhabditis elegans. I will begin by using fluorescent sensors that enable a real-time assessment of proteostasis in a living organism to identify sensor interaction with the proteostasis network in muscle cells. I will then perform cross-tissue analyses of sensor interactions with the proteostasis networks in neuronal and intestinal cells. Finally, I will examine how the chronic expression of misfolded proteins influences sensor interactions with the proteostasis network. This approach will allow me to examine how protein interactions with the cellular proteostasis machinery are changed in response to an altered cellular environment and to determine how the resources of proteostasis are distributed in health and disease. I believe that the proposed research will have broad implications for elucidating the dynamics and limitations of the cellular proteostasis network in a living organism, with long-term implications for therapeutics.'

Introduzione (Teaser)

The health of a cell is linked in part to the integrity of its protein quality control machinery. Malfunctions can cause protein misfolding diseases such as Alzheimer's and Huntington's.

Descrizione progetto (Article)

Protein homeostasis, or proteostasis, prevents the accumulation of misfolded or aggregated proteins. The EU-funded project PROTEOSTASIS (Cell-type-specific modulation of protein homeostasis in health and disease) has investigated if this essential machinery is cell-specific or more generic in nature, each cell being equipped with the molecular equipment to deal with a range of proteomes.

The researchers used the free-living nematode worm Caenorhabditis elegans that has four bands of muscle cells running lengthways down the body, allowing movement. Using molecular tools and fluorescent reporters, they developed a strategy to delineate the chaperone network that keeps the folded proteins in the most stable state and fit for their normal biological functions.

Responsible for temperature-dependent motility defects, mutations in the temperature sensitive (ts) unc-45 gene cause disorganised muscle filaments in the body wall under restrictive conditions but normal muscle filaments organization under permissive conditions. Using this behaviour, the researchers went on to identify four genes. Treatment with gene silencing interference RNA for the genes had no effect on the wild type worms, but had a profound disabling effect in the mutant worms already at the permissive temperature as compared with mutants grown at the restrictive temperature.

Chaperones then may be specialised for a set of substrates to impact the folding function. PROTEOSTASIS results suggest that there is in part a cell-type specific set of chaperones that are adapted to the cell's needs.

Further investigation of the capacity of proteostasis in different tissues under various physiological and stress conditions shows that there is a strong decline in folding capacity in the transition to adulthood. However, this can be regulated by the reproductive system and by germline stem cell arrest.

Project results suggest that as proteostasis dysregulation is the main cause of age-related protein misfolding diseases, one fruitful research avenue would be understanding the nature of regulatory signals at transition to adulthood. This would give insight into how protein quality control systems are remodelled at that crucial stage.