Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.
Nat Biomed Eng. 2022 Jan;6(1):76-93. doi: 10.1038/s41551-021-00819-5. Epub 2022 Jan 6.
A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer's disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals' memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational-experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.
功能失调的线粒体清除减少是衰老和与年龄相关的神经退行性病理的共同特征，如阿尔茨海默病（AD）。治疗这种受损的线粒体自噬的策略将受益于鉴定线粒体自噬调节剂。在这里，我们报告了无监督机器学习（涉及分子结构的向量表示、药效团指纹和构象指纹）与跨物种方法的联合使用，用于筛选和实验验证新的诱导线粒体自噬的化合物。从天然存在的化合物库中，该工作流程使我们能够鉴定出 18 种小分子，其中两种有效的线粒体自噬诱导剂（山奈酚和瑞普藤宁）。在 AD 的线虫和啮齿动物模型中，我们表明，两种线粒体自噬诱导剂都增加了谷氨酸能和胆碱能神经元的存活和功能，消除了淀粉样β和tau 病理学，并改善了动物的记忆。我们的研究结果表明，在 AD 模型中存在一种跨物种的记忆丧失的保守机制，这种机制是由有缺陷的线粒体自噬介导的。计算-实验筛选和验证工作流程可能有助于发现有效的线粒体自噬调节剂，刺激神经元健康和大脑内稳态。
