Sharma Apoorv, Kumari Indu, Islam Asimul, Prakash Hridayesh, Prakash Amresh, Kumar Vijay
Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, UP, 201303, India.
Amity Institute of Integrative Sciences and Health, Amity University Haryana, Gurgaon, 122413, India.
Biochem Biophys Rep. 2025 Jun 24;43:102081. doi: 10.1016/j.bbrep.2025.102081. eCollection 2025 Sep.
Autophagy is an important cytoprotective process impaired in neurodegenerative diseases such as Alzheimer's disease. The initiation process is mediated by the protein kinase Unc-51-like kinase 1 (ULK1) complex. ATG101, a cytosolic protein, plays a pivotal role in initiating autophagy as a component of the ULK complex in mammalian cells. It is important to understand the regulatory processes of individual autophagy components under different conditions for the development of therapeutic interventions. The caloric restriction mimetics (CRMs) such as chlorogenic acid (CGA) and fisetin mimic the healthy outcomes of caloric restriction without decreasing caloric consumption, constituting promising therapeutic candidates for neuroprotection. We explored the ATG101 interactions of CGA and fisetin in this work. Molecular docking and molecular dynamics (MD) simulations were used to investigate the interactions of these CRMs with ATG101, evaluating binding stability and dynamics. To confirm these interactions, we conducted quantitative real-time PCR (qRT-PCR) in differentiated SHSY5Y cells, analyzing the effect of CGA and fisetin on ATG101 gene expression. Our results indicated that fisetin forms a more stable complex with ATG101 compared to CGA. Yet, at the transcriptional level, both CRMs stimulate the mRNA level of ATG101. Therefore, these CRMs can be responsible for their potential as autophagy inducers. These findings offer significant insights into the molecular processes through which CRMs may improve neurodegenerative diseases by triggering autophagy.
自噬是一种重要的细胞保护过程，在阿尔茨海默病等神经退行性疾病中会受损。起始过程由蛋白激酶Unc-51样激酶1（ULK1）复合物介导。ATG101是一种胞质蛋白，作为哺乳动物细胞中ULK复合物的一个组成部分，在自噬起始中起关键作用。了解不同条件下各个自噬组分的调控过程对于开发治疗干预措施很重要。热量限制模拟物（CRMs）如绿原酸（CGA）和非瑟酮可模拟热量限制的健康结果而不减少热量消耗，是有前景的神经保护治疗候选物。在这项工作中，我们探索了CGA和非瑟酮与ATG101的相互作用。使用分子对接和分子动力学（MD）模拟来研究这些CRMs与ATG101的相互作用，评估结合稳定性和动力学。为了证实这些相互作用，我们在分化的SHSY5Y细胞中进行了定量实时PCR（qRT-PCR），分析CGA和非瑟酮对ATG101基因表达的影响。我们的结果表明，与CGA相比，非瑟酮与ATG101形成更稳定的复合物。然而，在转录水平上，两种CRMs都刺激ATG101的mRNA水平。因此，这些CRMs可能具有自噬诱导剂的潜力。这些发现为CRMs通过触发自噬改善神经退行性疾病的分子过程提供了重要见解。
