A short peptide protects from age‐onset proteotoxicity

Aberrant protein aggregation jeopardizes 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 protein, 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 for the development of several disorders including HD, while minimally affecting lifespan. This protection was dependent on the activity of aging‐regulating transcription factors and associated with enhanced Aβ and polyQ35‐YFP aggregation. A transcriptomic analysis unveiled that the peptide modifies signaling pathways, thereby modulating 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. Short peptides have been shown to mitigate protein aggregation. We report here that the peptide MTADV protects model nematodes from the aggregation of toxic proteins that cause neurodegeneration in humans. This protection is conferred by the modulation of gene expression and the enhancement of protective protein aggregation. Accordingly, this peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies.