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The Pathological Mechanism of Neuronal Autophagy-Lysosome Dysfunction After Ischemic Stroke

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Abstract

The abnormal initiation of autophagy flux in neurons after ischemic stroke caused dysfunction of autophagy-lysosome, which not only led to autophagy flux blockage, but also resulted in autophagic death of neurons. However, the pathological mechanism of neuronal autophagy-lysosome dysfunction did not form a unified viewpoint until now. In this review, taking the autophagy lysosomal dysfunction of neurons as a starting point, we summarized the molecular mechanisms that led to neuronal autophagy lysosomal dysfunction after ischemic stroke, which would provide theoretical basis for the clinical treatment of ischemic stroke.

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References

  • Ahsan A, Liu M, Zheng Y, Yan W, Pan L, Li Y, Ma S, Zhang X, Cao M, Wu Z, Hu W, Chen Z, Zhang X (2021) Natural compounds modulate the autophagy with potential implication of stroke. Acta Pharm Sin B 11(7):1708–1720

    Article  CAS  PubMed  Google Scholar 

  • Benes P, Vetvicka V, Fusek M (2008) Cathepsin D—many functions of one aspartic protease. Crit Rev Oncol Hematol 68(1):12–28

    Article  PubMed Central  PubMed  Google Scholar 

  • Boontem P, Yamashima T (2021) Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys. PLoS ONE 16(11):e0245702

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bootman MD, Chehab T, Bultynck G, Parys JB, Rietdorf K (2018) The regulation of autophagy by calcium signals: do we have a consensus? Cell Calcium 70:32–46

    Article  CAS  PubMed  Google Scholar 

  • Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27(50):6434–6451

    Article  CAS  PubMed  Google Scholar 

  • Cang C, Aranda K, Seo YJ, Gasnier B, Ren D (2015) TMEM175 is an organelle K(+) channel regulating lysosomal function. Cell 162(5):1101–1112

    Article  CAS  PubMed  Google Scholar 

  • Chen JH, Kuo HC, Lee KF, Tsai TH (2015) Global proteomic analysis of brain tissues in transient ischemia brain damage in rats. Int J Mol Sci 16(6):11873–11891

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Choi JH, Pile-Spellman J (2018) Reperfusion changes after stroke and practical approaches for neuroprotection. Neuroimaging Clin N Am 28(4):663–682

    Article  PubMed  Google Scholar 

  • Choi JH, Poli S, Chen M, Nguyen TN, Saver JL, Matouk C, Pile-Spellman J (2020) Selective brain hypothermia in acute ischemic stroke: reperfusion without reperfusion injury. Front Neurol 11:594289

    Article  PubMed Central  PubMed  Google Scholar 

  • Colacurcio DJ, Nixon RA (2016) Disorders of lysosomal acidification—the emerging role of V-ATPase in aging and neurodegenerative disease. Ageing Res Rev 32:75–88

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Engin A, Engin AB (2021) N-methyl-d-aspartate receptor signaling-protein kinases crosstalk in cerebral ischemia. Adv Exp Med Biol 1275:259–283

    Article  CAS  PubMed  Google Scholar 

  • Fu X, Liu Y, Zhang H, Yu X, Wang X, Wu C, Yang J (2021) Pseudoginsenoside F11 ameliorates the dysfunction of the autophagy-lysosomal pathway by activating calcineurin-mediated TFEB nuclear translocation in neuron during permanent cerebral ischemia. Exp Neurol 338:113598

    Article  CAS  PubMed  Google Scholar 

  • Gabryel B, Kost A, Kasprowska D, Liber S, Machnik G, Wiaderkiewicz R, Łabuzek K (2014) AMP-activated protein kinase is involved in induction of protective autophagy in astrocytes exposed to oxygen-glucose deprivation. Cell Biol Int 38(10):1086–1097

    Article  CAS  PubMed  Google Scholar 

  • Gao F, Wang FG, Lyu RR, Xue F, Zhang J, Huo R (2018) SLC35E3 identified as a target of novel-m1061-5p via microRNA profiling of patients with cardiovascular disease. Mol Med Rep 17(4):5159–5167

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gerónimo-Olvera C, Montiel T, Rincon-Heredia R, Castro-Obregón S, Massieu L (2017) Autophagy fails to prevent glucose deprivation/glucose reintroduction-induced neuronal death due to calpain-mediated lysosomal dysfunction in cortical neurons. Cell Death Dis 8(6):e2911

    Article  PubMed Central  PubMed  Google Scholar 

  • Hossain MI, Marcus JM, Lee JH, Garcia PL, Singh V, Shacka JJ, Zhang J, Gropen TI, Falany CN, Andrabi SA (2021a) Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective. Autophagy 17(6):1330–1348

    Article  CAS  PubMed  Google Scholar 

  • Hossain MI, Marcus JM, Lee JH, Garcia PL, Singh V, Shacka JJ, Zhang J, Gropen TI, Falany CN, Andrabi SA (2021b) Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective. Autophagy 17(6):1330–1348

    Article  CAS  PubMed  Google Scholar 

  • Hou K, Xu D, Li F, Chen S, Li Y (2019) The progress of neuronal autophagy in cerebral ischemia stroke: mechanisms, roles and research methods. J Neurol Sci 400:72–82

    Article  PubMed  Google Scholar 

  • Hu HJ, Song M (2017) Disrupted ionic homeostasis in ischemic stroke and new therapeutic targets. J Stroke Cerebrovasc Dis 26(12):2706–2719

    Article  PubMed  Google Scholar 

  • Hu M, Li P, Wang C, Feng X, Geng Q, Chen W, Marthi M, Zhang W, Gao C, Reid W, Swanson J, Du W, Hume RI, Xu H (2022) Parkinson’s disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes. Cell 185(13):2292-2308.e2220

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hua R, Han S, Zhang N, Dai Q, Liu T, Li J (2018) cPKCγ-modulated sequential reactivation of mTOR inhibited autophagic flux in neurons exposed to oxygen glucose deprivation/reperfusion. Int J Mol Sci 19(5):1380

    Article  PubMed Central  PubMed  Google Scholar 

  • Hua R, Wei H, Liu C, Shi Z, Xing Y (2019) Phosphorylated mTORC1 represses autophagic-related mRNA translation in neurons exposed to ischemia–reperfusion injury. J Cell Biochem 120(9):15915–15923

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Ouyang Q, Zhu M, Yu H, Mei K, Liu R (2021) mTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation. Nat Commun 12(1):6622

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hubert V, Peschel A, Langer B, Gröger M, Rees A, Kain R (2016) LAMP-2 is required for incorporating syntaxin-17 into autophagosomes and for their fusion with lysosomes. Biol Open 5(10):1516–1529

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hurley JH, Young LN (2017) Mechanisms of autophagy initiation. Annu Rev Biochem 86:225–244

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hwang JY, Gertner M, Pontarelli F, Court-Vazquez B, Bennett MV, Ofengeim D, Zukin RS (2017) Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die. Cell Death Differ 24(2):317–329

    Article  CAS  PubMed  Google Scholar 

  • Ishida Y, Nayak S, Mindell JA, Grabe M (2013) A model of lysosomal pH regulation. J Gen Physiol 141(6):705–720

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jiang S, Li T, Ji T, Yi W, Yang Z, Wang S, Yang Y, Gu C (2018) AMPK: potential therapeutic target for ischemic stroke. Theranostics 8(16):4535–4551

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jiang T, Yu JT, Zhu XC, Wang HF, Tan MS, Cao L, Zhang QQ, Gao L, Shi JQ, Zhang YD, Tan L (2014) Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br J Pharmacol 171(13):3146–3157

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jinn S, Drolet RE, Cramer PE, Wong AH, Toolan DM, Gretzula CA, Voleti B, Vassileva G, Disa J, Tadin-Strapps M, Stone DJ (2017) TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation. Proc Natl Acad Sci U S A 114(9):2389–2394

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lin L, Wang X, Yu Z (2016) Ischemia–reperfusion injury in the brain: mechanisms and potential therapeutic strategies. Biochem Pharmacol (los Angel) 5(4):213

    Google Scholar 

  • Liu R, Zhi X, Zhong Q (2015) ATG14 controls SNARE-mediated autophagosome fusion with a lysosome. Autophagy 11(5):847–849

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu T, Han S, Dai Q, Zheng J, Liu C, Li S, Li J (2019a) IL-17A-mediated excessive autophagy aggravated neuronal ischemic injuries via Src-PP2B-mTOR pathway. Front Immunol 10:2952

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu W, Shang G, Yang S, Huang J, Xue X, Lin Y, Zheng Y, Wang X, Wang L, Lin R, Tao J, Chen L (2016) Electroacupuncture protects against ischemic stroke by reducing autophagosome formation and inhibiting autophagy through the mTORC1-ULK1 complex-Beclin1 pathway. Int J Mol Med 37(2):309–318

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Che X, Zhang H, Fu X, Yao Y, Luo J, Yang Y, Cai R, Yu X, Yang J, Zhou MS (2021) CAPN1 (Calpain1)-mediated impairment of autophagic flux contributes to cerebral ischemia-induced neuronal damage. Stroke 52(5):1809–1821

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Xue X, Zhang H, Che X, Luo J, Wang P, Xu J, Xing Z, Yuan L, Liu Y, Fu X, Su D, Sun S, Zhang H, Wu C, Yang J (2019b) Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia. Autophagy 15(3):493–509

    Article  PubMed  Google Scholar 

  • Liu YY, Zhang TY, Xue X, Liu DM, Zhang HT, Yuan LL, Liu YL, Yang HL, Sun SB, Zhang C, Xu HS, Wu CF, Yang JY (2017) Pseudoginsenoside-F11 attenuates cerebral ischemic injury by alleviating autophagic/lysosomal defects. CNS Neurosci Ther 23(7):567–579

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lu N, Li X, Tan R, An J, Cai Z, Hu X, Wang F, Wang H, Lu C, Lu H (2018) HIF-1α/Beclin1-mediated autophagy is involved in neuroprotection induced by hypoxic preconditioning. J Mol Neurosci 66(2):238–250

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ma Y, Pan X, Xu P, Mi Y, Wang W, Wu X, He Q, Liu X, Tang W, An HX (2017) Plasma microRNA alterations between EGFR-activating mutational NSCLC patients with and without primary resistance to TKI. Oncotarget 8(51):88529–88536

    Article  PubMed Central  PubMed  Google Scholar 

  • Mandalaneni K, Rayi A, Jillella DV (2022) Stroke reperfusion injury. StatPearls Publishing, Treasure Island

    Google Scholar 

  • Marques ARA, Di Spiezio A (2020) Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis. Autophagy 16(5):811–825

    Article  CAS  PubMed  Google Scholar 

  • Nagakannan P, Islam MI, Conrad M, Eftekharpour E (2021) Cathepsin B is an executioner of ferroptosis. Biochim Biophys Acta Mol Cell Res 1868(3):118928

    Article  CAS  PubMed  Google Scholar 

  • Ni Y, Gu WW, Liu ZH, Zhu YM, Rong JG, Kent TA, Li M, Qiao SG, An JZ, Zhang HL (2018) RIP1K contributes to neuronal and astrocytic cell death in ischemic stroke via activating autophagic-lysosomal pathway. Neuroscience 371:60–74

    Article  CAS  PubMed  Google Scholar 

  • Orellana-Urzúa S, Rojas I, Líbano L, Rodrigo R (2020) Pathophysiology of ischemic stroke: role of oxidative stress. Curr Pharm Des 26(34):4246–4260

    Article  PubMed  Google Scholar 

  • Pan J, Konstas AA, Bateman B, Ortolano GA, Pile-Spellman J (2007) Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology 49(2):93–102

    Article  PubMed  Google Scholar 

  • Prabhakaran S, Ruff I, Bernstein RA (2015) Acute stroke intervention: a systematic review. JAMA 313(14):1451–1462

    Article  CAS  PubMed  Google Scholar 

  • Sha S, Tan J, Miao Y, Zhang Q (2021) The role of autophagy in hypoxia-induced neuroinflammation. DNA Cell Biol 40(6):733–739

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Wang D, Zhang T, Lu X, Duan F, Ju L, Zhuang X, Jiang X (2020) Eugenol attenuates cerebral ischemia–reperfusion injury by enhancing autophagy via AMPK-mTOR-P70S6K pathway. Front Pharmacol 11:84

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Takáts S, Glatz G, Szenci G, Boda A, Horváth GV, Hegedűs K, Kovács AL, Juhász G (2018) Non-canonical role of the SNARE protein Ykt6 in autophagosome–lysosome fusion. PLoS Genet 14(4):e1007359

    Article  PubMed Central  PubMed  Google Scholar 

  • Tang Q, Gao P, Arzberger T, Höllerhage M, Herms J, Höglinger G, Koeglsperger T (2021) Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome–lysosome fusion. Cell Death Dis 12(10):854

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tian X, Teng J, Chen J (2021) New insights regarding SNARE proteins in autophagosome–lysosome fusion. Autophagy 17(10):2680–2688

    Article  CAS  PubMed  Google Scholar 

  • Turco E, Fracchiolla D, Martens S (2020) Recruitment and activation of the ULK1/Atg1 kinase complex in selective autophagy. J Mol Biol 432(1):123–134

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Villalpando Rodriguez GE, Torriglia A (2013) Calpain 1 induce lysosomal permeabilization by cleavage of lysosomal associated membrane protein 2. Biochim Biophys Acta 1833(10):2244–2253

    Article  CAS  PubMed  Google Scholar 

  • Wang M, Liang X, Cheng M, Yang L, Liu H, Wang X, Sai N, Zhang X (2019) Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke. Cell Death Dis 10(8):561

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wie J, Liu Z, Song H, Tropea TF, Yang L, Wang H, Liang Y, Cang C, Aranda K, Lohmann J, Yang J, Lu B, Chen-Plotkin AS, Luk KC, Ren D (2021) A growth-factor-activated lysosomal K(+) channel regulates Parkinson’s pathology. Nature 591(7850):431–437

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xian M, Cai J, Zheng K, Liu Q, Liu Y, Lin H, Liang S, Wang S (2021) Aloe-emodin prevents nerve injury and neuroinflammation caused by ischemic stroke via the PI3K/AKT/mTOR and NF-κB pathway. Food Funct 12(17):8056–8067

    Article  CAS  PubMed  Google Scholar 

  • Yaghoobi H, Babaei E, Hussen BM, Emami A (2021) EBST: an evolutionary multi-objective optimization based tool for discovering potential biomarkers in ovarian cancer. IEEE/ACM Trans Comput Biol Bioinform 18(6):2384–2393

    Article  CAS  PubMed  Google Scholar 

  • Yamashima T (2012) Hsp70.1 and related lysosomal factors for necrotic neuronal death. J Neurochem 120(4):477–494

    Article  CAS  PubMed  Google Scholar 

  • Yan M, Zhu W, Zheng X, Li Y, Tang L, Lu B, Chen W, Qiu P, Leng T, Lin S, Yan G, Yin W (2016) Effect of glutamate on lysosomal membrane permeabilization in primary cultured cortical neurons. Mol Med Rep 13(3):2499–2505

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yan W, Fan J, Zhang X, Song H, Wan R, Wang W, Yin Y (2021) Decreased neuronal synaptosome associated protein 29 contributes to poststroke cognitive impairment by disrupting presynaptic maintenance. Theranostics 11(10):4616–4636

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yuan D, Hu K, Loke CM, Teramoto H, Liu C, Hu B (2021) Interruption of endolysosomal trafficking leads to stroke brain injury. Exp Neurol 345:113827

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yuan D, Liu C, Hu B (2018) Dysfunction of membrane trafficking leads to ischemia–reperfusion injury after transient cerebral ischemia. Transl Stroke Res 9(3):215–222

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Wang Y, Pan RL, Li Y, Hu YQ, Xv H, Zhu C, Wang X, Yin JW, Ma KT, Zhao D (2021a) Neuritin attenuates oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal injury by promoting autophagic flux. Exp Cell Res 407(2):112832

    Article  CAS  PubMed  Google Scholar 

  • Zhang M, Lu H, Xie X, Shen H, Li X, Zhang Y, Wu J, Ni J, Li H, Chen G (2020a) TMEM175 mediates Lysosomal function and participates in neuronal injury induced by cerebral ischemia–reperfusion. Mol Brain 13(1):113

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang T, Jiang Y, Zhang S, Tie T, Cheng Y, Su X, Man Z, Hou J, Sun L, Tian M, Zhang Y, Li J, Ma Y (2020b) The association between homocysteine and ischemic stroke subtypes in Chinese: a meta-analysis. Medicine (baltim) 99(12):e19467

    Article  CAS  Google Scholar 

  • Zhang X, Wei M, Fan J, Yan W, Zha X, Song H, Wan R, Yin Y, Wang W (2021b) Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons. Autophagy 17(6):1519–1542

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Cao Y, Liu C (2020c) Autophagy and ischemic stroke. Adv Exp Med Biol 1207:111–134

    Article  CAS  PubMed  Google Scholar 

  • Zheng W, Shen C, Wang L, Rawson S, Xie WJ, Nist-Lund C, Wu J, Shen Z, Xia S, Holt JR, Wu H, Fu TM (2022) pH regulates potassium conductance and drives a constitutive proton current in human TMEM175. Sci Adv 8(12):eabm1568

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Presentation at a Conference Statement

The manuscript is an original work and has not been previously submitted or is under consideration for publication in another journal. The study complies with current ethical consideration.

Funding

This work was supported by Grants from the National Natural Science Foundation of China (Nos. 81960418, and 81860411), and Yunnan Applied Basic Research Projects Fund of Yunnan Provincial Department of Science and Technology (Nos. 202001AT070049, and 202101AU070151), and Doctoral Foundation of Kunming University of Science and Technology (No. KKSY201960010), and Natural Science Foundation of Sichuan Province of China (Grant No. 2023NSFSC1567).

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Authors and Affiliations

  1. Faculty of Medicine, Kunming University of Science and Technology, Kunming, 650500, China

    Guang-Sen Shi, Qi-Lin Qin, Cheng Huang, Zi-Rong Li, Zi-Han Wang, Yong-Yan Wang & Xiao-Ming Zhao

  2. Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China

    Xiu-Ying He

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  1. Guang-Sen Shi
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Contributions

Z-XM, H-XY participated in the guidance of the study and revision of the manuscript. S-GS, HC and Q-QL were responsible for the manuscript writing and revising. L-ZR, W-YY and W-ZH prepared figures 1–7. All authors reviewed the manuscript.

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Correspondence to Xiu-Ying He or Xiao-Ming Zhao.

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Shi, GS., Qin, QL., Huang, C. et al. The Pathological Mechanism of Neuronal Autophagy-Lysosome Dysfunction After Ischemic Stroke. Cell Mol Neurobiol 43, 3251–3263 (2023). https://doi.org/10.1007/s10571-023-01382-0

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