重度抑郁症（major depressive disorder，MDD）是一种常见且严重的精神障碍，持续的心境低落是其主要的临床特征。MDD的病因复杂且具有高度异质性，目前尚未被完全阐明。抗抑郁药物是MDD主要的治疗方式之一，目前仍存在起效慢、治愈率低、安全性有待提高、患者依从性不足等问题，也一定程度上也反映了人们对MDD发病机制认识的不足。自噬（autophagy）是一种重要的维持稳态的细胞降解机制，与泛素‒蛋白酶体系统一起维持细胞正常的新陈代谢。哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）是细胞自噬的重要调控因子。当细胞处于不良条件时，可以通过mTOR依赖性自噬通路或mTOR非依赖性自噬通路激活自噬。监测自噬水平的常用指标包括微管相关蛋白轻链3-Ⅱ （microtubule-associated protein light chain 3-Ⅱ，LC3-Ⅱ）、Bcl-2相互作用蛋白（Bcl-2 interacting coiled-coil protein 1，Beclin-1）和p62。近些年来，越来越多的研究提示，自噬信号通路异常可能参与了抑郁症的发展，抗抑郁治疗可能影响自噬，因此调控自噬信号通路可能是抑郁症有希望的治疗靶点。未来应加强中枢神经系统自噬信号通路的研究，为抑郁症与抗抑郁药物的机制研究提供更多可靠的证据。该文就mTOR依赖性自噬通路及mTOR非依赖性自噬通路与常见自噬标志物在抑郁症中的研究进展做一综述。
关键词：重度抑郁症
;
自噬
;
自噬通路
;
自噬标记物
Abstract
Major depressive disorder (MDD) is a very common and severe mental disorder. Persistent emotional distress is one of its main clinical symptoms. The etiology of MDD is complex and highly heterogeneous, and has not yet been clarified. Antidepressant is a kind of important method for the treatment of MDD. However, there are still some problems such as slow onset of effect, low cure rate, safety to be further improved, and low compliance, which also reflect people's lack of understanding of the pathogenesis of MDD. Autophagy is a mechanism of cell degradation, which plays an important role in maintaining the stabilization of homeostasis. Mammalian target of rapamycin (mTOR) is an important regulator of autophagy, and adverse conditions can activate autophagy through mTOR-dependent or mTOR-independent autophagy pathways. Microtubule-associated protein light chain 3-Ⅱ (LC3-Ⅱ), Bcl-2 interacting coiled-coil protein 1 (Beclin-1) and p62 are common to be used in the measurement of autophagy flux. In recent years, more and more studies have shown that impaired autophagy may be involved in the development of MDD and antidepressant treatment may affect autophagy. Therefore, regulating impaired autophagy pathways may be a promising target of antidepressant treatment. In the future, more attention should be paid to the study of autophagy signaling pathway in the central nervous system to provide more reliable evidence for the mechanism of MDD and antidepressant treatment. This article introduces the roles of common mTOR-dependent autophagy pathways, mTOR-independent autophagy pathways and autophagic markers in the progression and treatment of MDD.
LI Siyuan, HE Shen, LI Huafang. Recent advance in autophagy-related pathways and key biomarkers in major depressive disorder. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2023, 43(10): 1324-1331 doi:10.3969/j.issn.1674-8115.2023.10.015
尽管目前多数证据基于细胞和动物模型，仍有临床数据分析发现多个自噬基因（如GPR18、PDK4、NRG1和EPHB2基因［16］）可能是MDD的潜在诊断标志物，自噬标志物［如MDD患者血清Bcl-2相互作用蛋白（Bcl-2 interacting coiled-coil protein 1，Beclin-1）］的基线表达水平［17］或表达水平的变化是抗抑郁药物潜在的疗效预测标志物。由此可见，自噬在MDD中起到了重要的作用，或可为新型抗抑郁药研发提供思路。下面就自噬信号通路的mTOR依赖性自噬通路及mTOR非依赖性自噬通路与常见自噬标志物做一综述［18］。
1 自噬相关信号通路
1.1 mTOR依赖性信号通路
哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路可通过调节自噬、促进蛋白合成、诱导神经再生发挥神经保护作用［19］。在人体内，mTOR可参与形成2种不同形式蛋白复合物，即哺乳动物雷帕霉素靶蛋白复合物1（mammalian target of rapamycin complex 1，mTORC1）及mTORC2，对多种细胞刺激作出应答［20］。mTORC1是自噬的关键分子，含有RAPTOR（regulatory-associated protein of mTOR）蛋白，表现为对雷帕霉素敏感；mTORC2则表现为对雷帕霉素不敏感。mTORC1［21］可正调控如蛋白激酶B（protein kinase B，PKB，Akt）、丝裂原激活通路激酶（mitogen-activated protein kinase，MAPK）等抑制自噬的信号通路分子，负调控如腺苷酸活化蛋白激酶（adenosine monophosphate-activated kinase，AMPK）等促进自噬的信号通路分子。
PI3K是自噬的一个主要负性调控节点：接受细胞外刺激，进而激活下游的自噬关键调节因子AKT/mTOR。PI3K/AKT/mTOR信号通路则是一条广泛存在于各种细胞中的经典自噬负性调控通路，目前研究认为其可以在多个节点调控神经元突触可塑性［39］。第10号染色体缺失的磷酸酶和张力蛋白同源物（phosphatase and tensin homolog，PTEN）是PI3K/AKT通路的一个重要负性调控分子，也是自噬的重要正性调控因子。
The original manuscript was drafted by LI Siyuan. The revision of the manuscript was reviewed and guided by HE Shen and LI Huafang. All the authors have read the last version of paper and consented for submission.
利益冲突声明
所有作者声明不存在利益冲突。
All authors disclose no relevant conflict of interests.
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... 尽管目前多数证据基于细胞和动物模型，仍有临床数据分析发现多个自噬基因（如GPR18、PDK4、NRG1和EPHB2基因［16］）可能是MDD的潜在诊断标志物，自噬标志物［如MDD患者血清Bcl-2相互作用蛋白（Bcl-2 interacting coiled-coil protein 1，Beclin-1）］的基线表达水平［17］或表达水平的变化是抗抑郁药物潜在的疗效预测标志物.由此可见，自噬在MDD中起到了重要的作用，或可为新型抗抑郁药研发提供思路.下面就自噬信号通路的mTOR依赖性自噬通路及mTOR非依赖性自噬通路与常见自噬标志物做一综述［18］. ...
1
... 尽管目前多数证据基于细胞和动物模型，仍有临床数据分析发现多个自噬基因（如GPR18、PDK4、NRG1和EPHB2基因［16］）可能是MDD的潜在诊断标志物，自噬标志物［如MDD患者血清Bcl-2相互作用蛋白（Bcl-2 interacting coiled-coil protein 1，Beclin-1）］的基线表达水平［17］或表达水平的变化是抗抑郁药物潜在的疗效预测标志物.由此可见，自噬在MDD中起到了重要的作用，或可为新型抗抑郁药研发提供思路.下面就自噬信号通路的mTOR依赖性自噬通路及mTOR非依赖性自噬通路与常见自噬标志物做一综述［18］. ...
1
... 尽管目前多数证据基于细胞和动物模型，仍有临床数据分析发现多个自噬基因（如GPR18、PDK4、NRG1和EPHB2基因［16］）可能是MDD的潜在诊断标志物，自噬标志物［如MDD患者血清Bcl-2相互作用蛋白（Bcl-2 interacting coiled-coil protein 1，Beclin-1）］的基线表达水平［17］或表达水平的变化是抗抑郁药物潜在的疗效预测标志物.由此可见，自噬在MDD中起到了重要的作用，或可为新型抗抑郁药研发提供思路.下面就自噬信号通路的mTOR依赖性自噬通路及mTOR非依赖性自噬通路与常见自噬标志物做一综述［18］. ...
1
... 哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路可通过调节自噬、促进蛋白合成、诱导神经再生发挥神经保护作用［19］.在人体内，mTOR可参与形成2种不同形式蛋白复合物，即哺乳动物雷帕霉素靶蛋白复合物1（mammalian target of rapamycin complex 1，mTORC1）及mTORC2，对多种细胞刺激作出应答［20］.mTORC1是自噬的关键分子，含有RAPTOR（regulatory-associated protein of mTOR）蛋白，表现为对雷帕霉素敏感；mTORC2则表现为对雷帕霉素不敏感.mTORC1［21］可正调控如蛋白激酶B（protein kinase B，PKB，Akt）、丝裂原激活通路激酶（mitogen-activated protein kinase，MAPK）等抑制自噬的信号通路分子，负调控如腺苷酸活化蛋白激酶（adenosine monophosphate-activated kinase，AMPK）等促进自噬的信号通路分子. ...
1
... 哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路可通过调节自噬、促进蛋白合成、诱导神经再生发挥神经保护作用［19］.在人体内，mTOR可参与形成2种不同形式蛋白复合物，即哺乳动物雷帕霉素靶蛋白复合物1（mammalian target of rapamycin complex 1，mTORC1）及mTORC2，对多种细胞刺激作出应答［20］.mTORC1是自噬的关键分子，含有RAPTOR（regulatory-associated protein of mTOR）蛋白，表现为对雷帕霉素敏感；mTORC2则表现为对雷帕霉素不敏感.mTORC1［21］可正调控如蛋白激酶B（protein kinase B，PKB，Akt）、丝裂原激活通路激酶（mitogen-activated protein kinase，MAPK）等抑制自噬的信号通路分子，负调控如腺苷酸活化蛋白激酶（adenosine monophosphate-activated kinase，AMPK）等促进自噬的信号通路分子. ...
1
... 哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路可通过调节自噬、促进蛋白合成、诱导神经再生发挥神经保护作用［19］.在人体内，mTOR可参与形成2种不同形式蛋白复合物，即哺乳动物雷帕霉素靶蛋白复合物1（mammalian target of rapamycin complex 1，mTORC1）及mTORC2，对多种细胞刺激作出应答［20］.mTORC1是自噬的关键分子，含有RAPTOR（regulatory-associated protein of mTOR）蛋白，表现为对雷帕霉素敏感；mTORC2则表现为对雷帕霉素不敏感.mTORC1［21］可正调控如蛋白激酶B（protein kinase B，PKB，Akt）、丝裂原激活通路激酶（mitogen-activated protein kinase，MAPK）等抑制自噬的信号通路分子，负调控如腺苷酸活化蛋白激酶（adenosine monophosphate-activated kinase，AMPK）等促进自噬的信号通路分子. ...
1
... 哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路可通过调节自噬、促进蛋白合成、诱导神经再生发挥神经保护作用［19］.在人体内，mTOR可参与形成2种不同形式蛋白复合物，即哺乳动物雷帕霉素靶蛋白复合物1（mammalian target of rapamycin complex 1，mTORC1）及mTORC2，对多种细胞刺激作出应答［20］.mTORC1是自噬的关键分子，含有RAPTOR（regulatory-associated protein of mTOR）蛋白，表现为对雷帕霉素敏感；mTORC2则表现为对雷帕霉素不敏感.mTORC1［21］可正调控如蛋白激酶B（protein kinase B，PKB，Akt）、丝裂原激活通路激酶（mitogen-activated protein kinase，MAPK）等抑制自噬的信号通路分子，负调控如腺苷酸活化蛋白激酶（adenosine monophosphate-activated kinase，AMPK）等促进自噬的信号通路分子. ...
1
... 哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路可通过调节自噬、促进蛋白合成、诱导神经再生发挥神经保护作用［19］.在人体内，mTOR可参与形成2种不同形式蛋白复合物，即哺乳动物雷帕霉素靶蛋白复合物1（mammalian target of rapamycin complex 1，mTORC1）及mTORC2，对多种细胞刺激作出应答［20］.mTORC1是自噬的关键分子，含有RAPTOR（regulatory-associated protein of mTOR）蛋白，表现为对雷帕霉素敏感；mTORC2则表现为对雷帕霉素不敏感.mTORC1［21］可正调控如蛋白激酶B（protein kinase B，PKB，Akt）、丝裂原激活通路激酶（mitogen-activated protein kinase，MAPK）等抑制自噬的信号通路分子，负调控如腺苷酸活化蛋白激酶（adenosine monophosphate-activated kinase，AMPK）等促进自噬的信号通路分子. ...
