The nucleolus structure of the cell is where ribosomes are built, but it appears to be influential in a range of mechanisms relating to stress response, quality control, and damage repair in cells. All of these are in turn linked to pace of aging. The relationships are by no means fully understood in detail, however. This is an area of ongoing exploration in which researchers are finding ways to adjust nucleolar function to slow aging in model organisms such as yeast and nematode worms.
To cope with hazardous protein toxicity (proteotoxicity), protein quality control mechanisms act in concert to supervise the integrity of nascent and mature proteins and direct terminally damaged proteins for degradation. In the early stages of life, this protein homeostasis (proteostasis) network successfully maintains the integrity of the proteome; however, with ageing, misfolded proteins aggregate and accumulate within and outside cells. These aggregates challenge the proteostasis network and often underlie the development of disorders known as 'proteinopathies', including neurodegenerative conditions.
Accordingly, the maintenance of proteostasis through late stages of life bears the promise to delay the emergence of these devastating diseases. Yet the identification of proteostasis regulators is needed to assess the feasibility of this approach. Here we report that knocking down the activity of the nucleolar FIB-1-NOL-56 complex protects model nematodes from proteotoxicity of the Alzheimer's disease-causing amyloid-β peptide and of abnormally long poly-glutamine stretches. This mechanism promotes proteostasis across tissues by modulating the activity of TGFβ signalling and by enhancing proteasome activity. Our findings point at research avenues towards the development of proteostasis-promoting therapies for neurodegenerative maladies.
Link: https://doi.org/10.1038/s41556-024-01564-y
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