A Short Peptide Protects from Age-Onset Proteotoxicity

Aberrant protein aggregation jeopardize cellular functionality and underlies the development of a myriad of late-onset maladies including Alzheimer’s disease (AD) and Huntington’s disease (HD). Accordingly, molecules that mitigate the toxicity of hazardous protein aggregates are of great interest as potential future therapeutics. Here we asked whether a small peptide, composed of five amino acids (5MER peptide) that was derived from the human pro-inflammatory CD44, could protect model nematodes from the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. We found that the 5MER peptide mitigates the toxicity that stems from both, the AD-causing Aβ peptide and a stretch of poly-glutamine that is accountable to the development of several disorders including HD, without affecting lifespan. This protection was dependent on the activity of the aging-regulating transcription factors and associated with enhanced Aβ and polyQ35-YFP aggregation. A transcriptomic analysis unveiled that the peptide modulates the expression of various genes including these which are known as protein homeostasis (proteostasis) regulators such as txt-13, and modifiers of proteasome activity. The knockdown of txt-13 protects worms from proteotoxicity to the same extent as the 5MER peptide, suggesting that the peptide activates the transcellular chaperone signaling to promote proteostasis. Together, our results propose that the 5MER peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies. Four synchronized groups of CL2006 worms (expressing Aβ) were included in the experiment: (i) animals that were grown on EV bacteria and were either exposed to the buffer (EV0, control) or (ii) treated with the 5MER peptide (EVP). These worms express Aβ uninterruptedly and thus, were challenged by high levels of proteotoxicity. (iii) Aβ RNAi-treated CL2006 worms that were either exposed to the buffer (AB0), or (iv) treated with the 5MER peptide (ABP). In the two latter groups (iii and iv) the expression of Aβ is largely suppressed and the animals are not challenged by a severe proteotoxic stress.