The Lautenberg Center of Immunology and Cancer Research, The Institute for Medical Research Israel - Canada (IMRIC), The Hebrew University School of Medicine, Jerusalem, Israel.
Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel - Canada (IMRIC), The Hebrew University School of Medicine, Jerusalem, Israel.
Aging Cell. 2023 Dec;22(12):e14013. doi: 10.1111/acel.14013. Epub 2023 Oct 27.
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.
异常蛋白聚集危及细胞功能，是包括阿尔茨海默病（AD）和亨廷顿病（HD）在内的多种迟发性疾病的发病基础。因此，能够减轻危险蛋白聚集毒性的分子作为潜在的未来治疗方法引起了人们的极大兴趣。在这里，我们询问了一种由五个氨基酸组成的小肽（5MER 肽），它来源于人类促炎 CD44 蛋白，是否可以保护模型线虫免受导致神经退行性疾病的聚集蛋白的毒性影响。我们发现，5MER 肽可以减轻源自 AD 致病 Aβ肽和一段多聚谷氨酰胺的毒性，而对寿命的影响最小。这种保护依赖于衰老调节转录因子的活性，并与增强的 Aβ和 polyQ35-YFP 聚集有关。转录组分析显示，该肽修饰了信号通路，从而调节了各种基因的表达，包括已知的蛋白质稳态（蛋白稳态）调节剂，如 txt-13 和蛋白酶体活性调节剂。txt-13 的敲低可以在与 5MER 肽相同的程度上保护蠕虫免受蛋白毒性，这表明该肽激活了细胞间伴侣信号以促进蛋白稳态。总之，我们的结果表明，5MER 肽应该被认为是治疗神经退行性疾病的未来治疗鸡尾酒的一个组成部分。
