Two human metabolites rescue a C. elegans model of Alzheimer's disease via a cytosolic unfolded protein response.
Two human metabolites rescue a C. elegans model of Alzheimer's disease via a cytosolic unfolded protein response.
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两种人类代谢产物拯救了一个C。elegans模型的阿尔茨海默病通过胞质未折叠蛋白质反应。
DOI：
10.1038/s42003-021-02218-7
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发表时间：
2021-07-07
影响因子：
5.9
通讯作者：
Vendruscolo M
中科院分区：
文献类型：
--
作者：
Joshi P;Perni M;Limbocker R;Mannini B;Casford S;Chia S;Habchi J;Labbadia J;Dobson CM;Vendruscolo M
与年龄相关的细胞代谢变化会影响大脑的内稳态，为阿尔茨海默病和帕金森病等神经退行性疾病的发生和发展创造条件。尽管代谢物在细胞信号通路中的作用已被广泛研究，但它们对蛋白质聚集的影响仍相对未被探索。通过计算分析人类代谢组数据库，我们发现了两种内源性代谢物，肌肽和犬尿酸，它们抑制淀粉样蛋白β肽（a β）的聚集，并挽救了秀丽隐线虫的阿尔茨海默病模型。我们发现这些代谢物通过转录因子HSF-1和下游伴侣HSP40/ j蛋白DNJ-12和DNJ-19触发细胞质内未折叠蛋白反应。这些结果通过提供这些代谢物的作用机制，有助于合理化先前关于这些代谢物可能具有抗衰老益处的观察结果。综上所述，我们的研究结果提供了代谢物稳态和蛋白质稳态之间的联系，这可能会激发对神经退行性疾病的预防性干预。Joshi等人发现了两种人体代谢物，肌肽和犬尿酸，通过抑制体内淀粉样蛋白-肽的聚集来拯救秀丽隐杆线虫的阿尔茨海默病模型。他们发现这些代谢物通过转录因子HSF-1和分子伴侣DNJ-12和DNJ-19触发细胞质内未折叠蛋白反应，从而提供代谢物稳态和蛋白质稳态之间的机制联系，从而进一步了解神经退行性疾病的干预措施。
Age-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders. Joshi et al. identify two human metabolites, carnosine and kynurenic acid, that rescue a C. elegans model of Alzheimer’s disease by inhibiting the aggregation of the amyloid beta peptide in vivo. They find that these metabolites trigger a cytosolic unfolded protein response through the transcription factor HSF-1 and molecular chaperones DNJ-12 and DNJ-19, thus providing mechanistic links between metabolite homeostasis and protein homeostasis to further insights into interventions against neurodegenerative diseases.
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