A Nucleolar Mechanism Suppresses Organismal Proteostasis by Modulating Signaling of the TGF-β/ERK Axis

The protein homeostasis (proteostasis) network encompasses a myriad of mechanisms that maintain the integrity of the proteome by controlling various biological functions, including protein folding and degradation. Alas, aging-associated decline in the efficiency of this network enables protein aggregation and consequently the development of late onset neurodegenerative disorders, such as Alzheimer’s disease (AD). 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 AD-causing, Aβ peptide. This mechanism promotes proteostasis across tissues by modulating the activity of TGF-β signaling and by enhancing proteasome activity. Our findings point at new research avenues toward the development of proteostasis-promoting therapies for neurodegenerative maladies. Three synchronized groups of CL2006 worms (expressing Aβ) were included in the experiment: Animals after hatching were grown on EV bacteria until L4 larva stage then separate into different goups: (i) animals that were grown on EV bacteria or (ii) treated with nol-56 RNAi. These worms express Aβ uninterruptedly and thus, were challenged by high levels of proteotoxicity.