Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Zhejiang, China.
Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Zhejiang, China.
Pharmacol Ther. 2024 Nov;263:108729. doi: 10.1016/j.pharmthera.2024.108729. Epub 2024 Oct 12.
Autophagy functions as the primary cellular mechanism for clearing unwanted intracellular contents. Emerging evidence suggests that the selective elimination of intracellular organelles through autophagy, compared to the increased bulk autophagic flux, is crucial for the pathological progression of central nervous system (CNS) disorders. Notably, autophagic removal of mitochondria, known as mitophagy, is well-understood in an unhealthy brain. Accumulated data indicate that selective autophagy of other substrates, including protein aggregates, liposomes, and endoplasmic reticulum, plays distinctive roles in various pathological stages. Despite variations in substrates, the molecular mechanisms governing selective autophagy can be broadly categorized into two types: ubiquitin-dependent and -independent pathways, both of which can be subjected to regulation by small-molecule compounds. Notably, natural products provide the remarkable possibility for future structural optimization to regulate the highly selective autophagic clearance of diverse substrates. In this context, we emphasize the selectivity of autophagy in regulating CNS disorders and provide an overview of chemical compounds capable of modulating selective autophagy in these disorders, along with the underlying mechanisms. Further exploration of the functions of these compounds will in turn advance our understanding of autophagic contributions to brain disorders and illuminate precise therapeutic strategies for these diseases.
自噬作为清除细胞内不需要的物质的主要细胞机制。新出现的证据表明，通过自噬选择性地消除细胞内细胞器，而不是增加批量自噬通量，对于中枢神经系统 (CNS) 疾病的病理进展至关重要。值得注意的是，线粒体的自噬清除，即自噬，在不健康的大脑中得到了很好的理解。积累的数据表明，包括蛋白质聚集体、脂滴和内质网在内的其他底物的选择性自噬在各种病理阶段中发挥着独特的作用。尽管底物存在差异，但控制选择性自噬的分子机制可以大致分为两类：泛素依赖性和非依赖性途径，两者都可以受到小分子化合物的调节。值得注意的是，天然产物为未来的结构优化提供了显著的可能性，以调节对多种底物的高度选择性自噬清除。在这种情况下，我们强调自噬在调节中枢神经系统疾病中的选择性，并概述了能够调节这些疾病中选择性自噬的化学化合物及其潜在机制。进一步探索这些化合物的功能将有助于我们了解自噬对脑疾病的贡献，并为这些疾病阐明精确的治疗策略。
