收稿日期: 2023-04-10
录用日期: 2023-06-29
网络出版日期: 2023-10-28
基金资助
上海市精神心理疾病临床医学研究中心项目(19MC1911100);上海市精神卫生中心院级重点课题(2022zd02)
Recent advance in autophagy-related pathways and key biomarkers in major depressive disorder
Received date: 2023-04-10
Accepted date: 2023-06-29
Online published: 2023-10-28
Supported by
Project of Shanghai Clinical Research Center for Mental Health(19MC1911100);Shanghai Mental Health Center Fund(2022zd02)
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。
李偲媛 , 和申 , 李华芳 . 重度抑郁症中自噬通路及其关键标志物的研究进展[J]. 上海交通大学学报（医学版）, 2023 , 43(10) : 1324 -1331 . DOI: 10.3969/j.issn.1674-8115.2023.10.015
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.
| 1 | DWYER J B, AFTAB A, RADHAKRISHNAN R, et al. Hormonal treatments for major depressive disorder: state of the art[J]. Am J Psychiatry, 2020, 177(8): 686-705. |
| 2 | GASSEN N C, REIN T. Is there a role of autophagy in depression and antidepressant action?[J]. Front Psychiatry, 2019, 10: 337. |
| 3 | KAMRAN M, BIBI F, REHMAN A U, et al. Major depressive disorder: existing hypotheses about pathophysiological mechanisms and new genetic findings[J]. Genes, 2022, 13(4): 646. |
| 4 | 罗澜, 石真玉, 赖水琴, 等. 抗抑郁药的全球管线和研发趋势分析[J]. 中国新药杂志, 2023, 32(3): 217-223. |
| 4 | LUO L, SHI Z Y, LAI S Q, et al. Analysis of the global pipeline and development trend of antidepressants[J]. Chinese Journal of New Drugs, 2023, 32(3): 217-223. |
| 5 | JARO?CZYK M, WALORY J. Novel molecular targets of antidepressants[J]. Molecules, 2022, 27(2): 533. |
| 6 | GONDA X, DOME P, NEILL J C, et al. Novel antidepressant drugs: beyond monoamine targets[J]. CNS Spectr, 2023, 28(1): 6-15. |
| 7 | WANG Q Z, DWIVEDI Y. Advances in novel molecular targets for antidepressants[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2021, 104: 110041. |
| 8 | MA Q Q, LONG S H, GAN Z D, et al. Transcriptional and post-transcriptional regulation of autophagy[J]. Cells, 2022, 11(3): 441. |
| 9 | FLEMING A, BOURDENX M, FUJIMAKI M, et al. The different autophagy degradation pathways and neurodegeneration[J]. Neuron, 2022, 110(6): 935-966. |
| 10 | FRIES G R, SALDANA V A, FINNSTEIN J, et al. Molecular pathways of major depressive disorder converge on the synapse[J]. Mol Psychiatry, 2023, 28(1): 284-297. |
| 11 | FLEMING A, RUBINSZTEIN D C. Autophagy in neuronal development and plasticity[J]. Trends Neurosci, 2020, 43(10): 767-779. |
| 12 | KUIJPERS M, HAUCKE V. Neuronal autophagy controls the axonal endoplasmic reticulum to regulate neurotransmission in healthy neurons[J]. Autophagy, 2021, 17(4): 1049-1051. |
| 13 | HWANG H Y, SHIM J S, KIM D, et al. Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein[J]. Autophagy, 2021, 17(10): 2783-2799. |
| 14 | BAR-YOSEF T, DAMRI O, AGAM G. Dual role of autophagy in diseases of the central nervous system[J]. Front Cell Neurosci, 2019, 13: 196. |
| 15 | ZHOU Y F, TAO X, WANG Z, et al. Hippocampus metabolic disturbance and autophagy deficiency in olfactory bulbectomized rats and the modulatory effect of fluoxetine[J]. Int J Mol Sci, 2019, 20(17): 4282. |
| 16 | HE S, DENG Z F, LI Z, et al. Signatures of 4 autophagy-related genes as diagnostic markers of MDD and their correlation with immune infiltration[J]. J Affect Disord, 2021, 295: 11-20. |
| 17 | HE S, ZENG D, XU F K, et al. Baseline serum levels of beclin-1, but not inflammatory factors, may predict antidepressant treatment response in Chinese Han patients with MDD: a preliminary study[J]. Front Psychiatry, 2019, 10: 378. |
| 18 | AL-BARI M A A, XU P Y. Molecular regulation of autophagy machinery by mTOR-dependent and-independent pathways[J]. Ann N Y Acad Sci, 2020, 1467(1): 3-20. |
| 19 | 朱翠珍. GLT1-mTOR自噬调节机制在抑郁症和慢性疼痛共病中的机制研究[D]. 上海: 上海交通大学, 2018. |
| 19 | ZHU C Z. Mechanisms of GLT1-mTOR autophagy in the comorbidity of major depressive disorder and chronic pain[D]. Shanghai: Shanghai Jiao Tong University, 2018. |
| 20 | 高可润. mTOR信号通路基因多态性与精神分裂症易感性及药物效应的相关性探索研究[D]. 上海: 上海交通大学, 2016. |
| 20 | GAO K R. The exploratory study of the association between polymorphisms of mTOR pathway genes and susceptibility, the pharmacotherapy effects in schizophrenia[D]. Shanghai: Shanghai Jiao Tong University, 2016. |
| 21 | AN X Q, YAO X X, LI B J, et al. Role of BDNF-mTORC1 signaling pathway in female depression[J]. Neural Plast, 2021, 2021: 6619515. |
| 22 | TIAN Q, CHEN L, LUO B, et al. Hydrogen sulfide antagonizes chronic restraint stress-induced depressive-like behaviors via upregulation of adiponectin[J]. Front Psychiatry, 2018, 9: 399. |
| 23 | CHAUMONT-DUBEL S, DUPUY V, BOCKAERT J, et al. The 5-HT6 receptor interactome: new insight in receptor signaling and its impact on brain physiology and pathologies[J]. Neuropharmacology, 2020, 172: 107839. |
| 24 | HUANG Z H, HUANG X Y, WANG Q, et al. Extract of Euryale ferox Salisb exerts antidepressant effects and regulates autophagy through the adenosine monophosphate-activated protein kinase-UNC-51-like kinase 1 pathway[J]. IUBMB Life, 2018, 70(4): 300-309. |
| 25 | LYU D B, WANG F, ZHANG M K, et al. Ketamine induces rapid antidepressant effects via the autophagy-NLRP3 inflammasome pathway[J]. Psychopharmacology, 2022, 239(10): 3201-3212. |
| 26 | SHU X D, SUN Y M, SUN X Y, et al. The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression[J]. Cell Death Dis, 2019, 10(8): 577. |
| 27 | JEGGA A G, SCHNEIDER L, OUYANG X S, et al. Systems biology of the autophagy-lysosomal pathway[J]. Autophagy, 2011, 7(5): 477-489. |
| 28 | LUMENG C N, SALTIEL A R. Insulin htts on autophagy[J]. Autophagy, 2006, 2(3): 250-253. |
| 29 | BA L N, GAO J Q, CHEN Y P, et al. Allicin attenuates pathological cardiac hypertrophy by inhibiting autophagy via activation of PI3K/Akt/mTOR and MAPK/ERK/mTOR signaling pathways[J]. Phytomedicine, 2019, 58: 152765. |
| 30 | GAO W Q, WANG W, ZHANG J, et al. Allicin ameliorates obesity comorbid depressive-like behaviors: involvement of the oxidative stress, mitochondrial function, autophagy, insulin resistance and NOX/Nrf2 imbalance in mice[J]. Metab Brain Dis, 2019, 34(5): 1267-1280. |
| 31 | ABILDGAARD A, ELFVING B, HOKLAND M, et al. Probiotic treatment protects against the pro-depressant-like effect of high-fat diet in Flinders Sensitive Line rats[J]. Brain Behav Immun, 2017, 65: 33-42. |
| 32 | PORTOVEDO M, REGINATO A, MIYAMOTO J é, et al. Lipid excess affects chaperone-mediated autophagy in hypothalamus[J]. Biochimie, 2020, 176: 110-116. |
| 33 | SONG J, LEE B, KANG S, et al. Agmatine ameliorates high glucose-induced neuronal cell senescence by regulating the p21 and p53 signaling[J]. Exp Neurobiol, 2016, 25(1): 24-32. |
| 34 | KALE M, NIMJE N, AGLAWE M M, et al. Agmatine modulates anxiety and depression-like behaviour in diabetic insulin-resistant rats[J]. Brain Res, 2020, 1747: 147045. |
| 35 | XU W, LUO Y, YIN J X, et al. Targeting AMPK signaling by polyphenols: a novel strategy for tackling aging[J]. Food Funct, 2023, 14(1): 56-73. |
| 36 | KIM S H, YU H S, PARK S, et al. Electroconvulsive seizures induce autophagy by activating the AMPK signaling pathway in the rat frontal cortex[J]. Int J Neuropsychopharmacol, 2020, 23(1): 42-52. |
| 37 | LI Y, CHENG Y J, ZHOU Y, et al. High fat diet-induced obesity leads to depressive and anxiety-like behaviors in mice via AMPK/mTOR-mediated autophagy[J]. Exp Neurol, 2022, 348: 113949. |
| 38 | HUANG X Y, WU H R, JIANG R Z, et al. The antidepressant effects of ɑ-tocopherol are related to activation of autophagy via the AMPK/mTOR pathway[J]. Eur J Pharmacol, 2018, 833: 1-7. |
| 39 | 张治楠, 梁丽艳, 连嘉惠, 等. 中枢神经系统PI3K/AKT/mTOR信号通路研究进展[J]. 实用医学杂志, 2020, 36(5): 689-694. |
| 39 | ZHANG Z N, LIANG L Y, LIAN J H, et al. PI3K/AKT/mTOR signaling pathway in central nervous system[J]. Journal of Practical Medicine, 2020, 36(5): 689-694. |
| 40 | KAREGE F, PERROUD N, BURKHARDT S, et al. Alterations in phosphatidylinositol 3-kinase activity and PTEN phosphatase in the prefrontal cortex of depressed suicide victims[J]. Neuropsychobiology, 2011, 63(4): 224-231. |
| 41 | XIAO X, SHANG X L, ZHAI B H, et al. Nicotine alleviates chronic stress-induced anxiety and depressive-like behavior and hippocampal neuropathology via regulating autophagy signaling[J]. Neurochem Int, 2018, 114: 58-70. |
| 42 | KAREGE F, PERROUD N, BURKHARDT S, et al. Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3beta in ventral prefrontal cortex of depressed suicide victims[J]. Biol Psychiatry, 2007, 61(2): 240-245. |
| 43 | YANG Y, HU Z Y, DU X X, et al. miR-16 and fluoxetine both reverse autophagic and apoptotic change in chronic unpredictable mild stress model rats[J]. Front Neurosci, 2017, 11: 428. |
| 44 | AMIN N, XIE S Y, TAN X N, et al. Optimized integration of fluoxetine and 7, 8-dihydroxyflavone as an efficient therapy for reversing depressive-like behavior in mice during the perimenopausal period[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2020, 101: 109939. |
| 45 | SHIN C, KIM Y K. Ketamine in major depressive disorder: mechanisms and future perspectives[J]. Psychiatry Investig, 2020, 17(3): 181-192. |
| 46 | ZHANG Q, WANG X B, CAO S J, et al. Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways[J]. Biomedecine Pharmacother, 2020, 128: 110245. |
| 47 | KALRA P, KHAN H, KAUR A, et al. Mechanistic insight on autophagy modulated molecular pathways in cerebral ischemic injury: from preclinical to clinical perspective[J]. Neurochem Res, 2022, 47(4): 825-843. |
| 48 | D'ORAZI G, CORDANI M, CIRONE M. Oncogenic pathways activated by pro-inflammatory cytokines promote mutant p53 stability: clue for novel anticancer therapies[J]. Cell Mol Life Sci, 2021, 78(5): 1853-1860. |
| 49 | HE J, REN Z K, XIA W S, et al. Identification of key genes and crucial pathways for major depressive disorder using peripheral blood samples and chronic unpredictable mild stress rat models[J]. PeerJ, 2021, 9: e11694. |
| 50 | ALI T, RAHMAN S U, HAO Q, et al. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation[J]. J Pineal Res, 2020, 69(2): e12667. |
| 51 | CHEN Y, SHI J B, LIU H Y, et al. Plasma microRNA array analysis identifies overexpressed miR-19b-3p as a biomarker of bipolar depression distinguishing from unipolar depression[J]. Front Psychiatry, 2020, 11: 757. |
| 52 | RANA T, BEHL T, SEHGAL A, et al. Elucidating the possible role of FoxO in depression[J]. Neurochem Res, 2021, 46(11): 2761-2775. |
| 53 | PERRONE M, PATERGNANI S, MAMBRO T D, et al. Calcium homeostasis in the control of mitophagy[J]. Antioxid Redox Signal, 2023, 38(7/8/9): 581-598. |
| 54 | HU Y X, HAN X S, JING Q. Ca(2+) ion and autophagy[J]. Adv Exp Med Biol, 2019, 1206: 151-166. |
| 55 | JI J, LI S Z, JIANG Z K, et al. Activating PPARβ/δ protects against endoplasmic reticulum stress-induced astrocytic apoptosis via UCP2-dependent mitophagy in depressive model[J]. Int J Mol Sci, 2022, 23(18): 10822. |
| 56 | PE?A-MARTINEZ C, RICKMAN A D, HECKMANN B L. Beyond autophagy: lc3-associated phagocytosis and endocytosis[J]. Sci Adv, 2022, 8(43): eabn1702. |
| 57 | PRERNA K, DUBEY V K. Beclin1-mediated interplay between autophagy and apoptosis: new understanding[J]. Int J Biol Macromol, 2022, 204: 258-273. |
| 58 | YE S, FANG L, XIE S Y, et al. Resveratrol alleviates postpartum depression-like behavior by activating autophagy via SIRT1 and inhibiting AKT/mTOR pathway[J]. Behav Brain Res, 2023, 438: 114208. |
| 59 | TRIPATHI A, SCAINI G, BARICHELLO T, et al. Mitophagy in depression: pathophysiology and treatment targets[J]. Mitochondrion, 2021, 61: 1-10. |
| 60 | ZSCHOCKE J, ZIMMERMANN N, BERNING B, et al. Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons: dissociation from cholesterol homeostasis[J]. Neuropsychopharmacology, 2011, 36(8): 1754-1768. |
| 61 | KORNHUBER J, GULBINS E. New molecular targets for antidepressant drugs[J]. Pharmaceuticals, 2021, 14(9): 894. |
| 62 | XIANG H G, ZHANG J F, LIN C C, et al. Targeting autophagy-related protein kinases for potential therapeutic purpose[J]. Acta Pharm Sin B, 2020, 10(4): 569-581. |
| 63 | ALCOCER-GóMEZ E, CASAS-BARQUERO N, Nú?EZ-VASCO J, et al. Psychological status in depressive patients correlates with metabolic gene expression[J]. CNS Neurosci Ther, 2017, 23(10): 843-845. |
| 64 | 宁爱玲, 何路遥, 曾端, 等. 抑郁障碍患者血浆Beclin 1水平分析[J]. 临床精神医学杂志, 2022, 32(4): 265-267. |
| 64 | NING A L, HE L Y, ZENG D, et al. Analysis of plasma Beclin 1 levels in patients with major depressive disorder[J]. Journal of Clinical Psychiatry, 2022, 32(4): 265-267 |
| 65 | YE X X, ZHU M M, CHE X H, et al. Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation[J]. J Neuroinflammation, 2020, 17(1): 18. |
| 66 | MOKHTARI T. Targeting autophagy and neuroinflammation pathways with plant-derived natural compounds as potential antidepressant agents[J]. Phytother Res, 2022, 36(9): 3470-3489. |
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