Cathepsin B Promotes Aß Proteotoxicity by Modulating Aging Regulating Mechanisms
While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer's disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid ß (Aß), is controversial. Using an activity based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aß proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aß toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aß–mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders. Overall design: Synchronized CL2006 worms (expressing Aß) were grown from egg onwards on E.Coli K12 strain HT115 (DE3) containing plasmids expressing (i) EV (Empty Vector) RNAi or (ii) cpr-6 RNAi. These worms were collected at Day6 of adulthood to perform RNA sequencing. This data  represents four biological repeats of this experimental design.