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Role of autophagy in the pathogenesis of multiple sclerosis

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Abstract

Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively influences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Inflammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-inflammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinflammation associated with the pathogenesis of MS.

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References

  1. Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006, 443: 780–786.

    Article  CAS  PubMed  Google Scholar 

  2. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med 2013, 19: 983–997.

    Article  CAS  PubMed  Google Scholar 

  3. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005, 64: 113–122.

    PubMed  Google Scholar 

  4. Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ. The role of autophagy in Parkinson's disease. Cold Spring Harb Perspect Med 2012, 2: a009357.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Song CY, Guo JF, Liu Y, Tang BS. Autophagy and its comprehensive impact on ALS. Int J Neurosci 2012, 122: 695–703.

    Article  CAS  PubMed  Google Scholar 

  6. Steinman L. Multiple sclerosis: a two-stage disease. Nat Immunol 2001, 2: 762–764.

    Article  CAS  PubMed  Google Scholar 

  7. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 2010, 140: 918–934.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Ben-Nun A, Wekerle H, Cohen IR. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 1981, 11: 195–199.

    Article  CAS  PubMed  Google Scholar 

  9. International Multiple Sclerosis Genetics C, Wellcome Trust Case Control C, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011, 476: 214–219.

    Article  Google Scholar 

  10. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005, 23: 683–747.

    Article  CAS  PubMed  Google Scholar 

  11. Fujinami RS, Oldstone MB. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 1985, 230: 1043–1045.

    Article  CAS  PubMed  Google Scholar 

  12. Stys PK, Zamponi GW, van Minnen J, Geurts JJ. Will the real multiple sclerosis please stand up? Nat Rev Neurosci 2012, 13: 507–514.

    Article  CAS  PubMed  Google Scholar 

  13. Ellwardt E, Zipp F. Molecular mechanisms linking neuroinflammation and neurodegeneration in MS. Exp Neurol 2014, 262 Pt A: 8–17.

    Article  CAS  PubMed  Google Scholar 

  14. Kang Z, Wang C, Zepp J, Wu L, Sun K, Zhao J, et al. Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2(+) glial cells. Nat Neurosci 2013, 16: 1401–1408.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Wellcome Trust Case Control C. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007, 447: 661–678.

    Article  Google Scholar 

  16. Zhou XJ, Lu XL, Lv JC, Yang HZ, Qin LX, Zhao MH, et al. Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population. Ann Rheum Dis 2011, 70: 1330–1337.

    Article  CAS  PubMed  Google Scholar 

  17. Xu H, Wu ZY, Fang F, Guo L, Chen D, Chen JX, et al. Genetic deficiency of Irgm1 (LRG-47) suppresses induction of experimental autoimmune encephalomyelitis by promoting apoptosis of activated CD4+ T cells. FASEB J 2010, 24: 1583–1592.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Stoffels JM, de Jonge JC, Stancic M, Nomden A, van Strien ME, Ma D, et al. Fibronectin aggregation in multiple sclerosis lesions impairs remyelination. Brain 2013, 136: 116–131.

    Article  PubMed  Google Scholar 

  19. David MA, Tayebi M. Detection of protein aggregates in brain and cerebrospinal fluid derived from multiple sclerosis patients. Front Neurol 2014, 5: 251.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Dasgupta A, Zheng J, Perrone-Bizzozero NI, Bizzozero OA. Increased carbonylation, protein aggregation and apoptosis in the spinal cord of mice with experimental autoimmune encephalomyelitis. ASN Neuro 2013, 5: e00111.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Kalman B, Laitinen K, Komoly S. The involvement of mitochondria in the pathogenesis of multiple sclerosis. J Neuroimmunol 2007, 188: 1–12.

    Article  CAS  PubMed  Google Scholar 

  22. Motori E, Puyal J, Toni N, Ghanem A, Angeloni C, Malaguti M, et al. Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell Metab 2013, 18: 844–859.

    Article  CAS  PubMed  Google Scholar 

  23. Lu Q, Zhang J, Allison R, Gay H, Yang WX, Bhowmick NA, et al. Identification of extracellular delta-catenin accumulation for prostate cancer detection. Prostate 2009, 69: 411–418.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Broadwater L, Pandit A, Clements R, Azzam S, Vadnal J, Sulak M, et al. Analysis of the mitochondrial proteome in multiple sclerosis cortex. Biochim Biophys Acta 2011, 1812: 630–641.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. van Horssen J, Witte ME, Schreibelt G, de Vries HE. Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta 2011, 1812: 141–150.

    Article  PubMed  Google Scholar 

  26. Chen Y, Gibson SB. Is mitochondrial generation of reactive oxygen species a trigger for autophagy? Autophagy 2008, 4: 246–248.

    Article  CAS  PubMed  Google Scholar 

  27. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ 2008, 15: 171–182.

    Article  CAS  PubMed  Google Scholar 

  28. Saitoh T, Akira S. Regulation of innate immune responses by autophagy-related proteins. J Cell Biol 2010, 189: 925–935.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, Lee H, et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci U S A 2009, 106: 20842–20846.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 2013, 13: 722–737.

    Article  CAS  PubMed  Google Scholar 

  31. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, et al. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 2012, 13: 255–263.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 2008, 456: 264–268.

    Article  CAS  PubMed  Google Scholar 

  33. Castillo EF, Dekonenko A, Arko-Mensah J, Mandell MA, Dupont N, Jiang S, et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc Natl Acad Sci U S A 2012, 109: E3168–3176.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Paul S, Kashyap AK, Jia W, He YW, Schaefer BC. Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-kappaB. Immunity 2012, 36: 947–958.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 2004, 119: 753–766.

    Article  CAS  PubMed  Google Scholar 

  36. Harris J, Keane J. How tumour necrosis factor blockers interfere with tuberculosis immunity. Clin Exp Immunol 2010, 161: 1–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T, et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 2005, 307: 593–596.

    Article  CAS  PubMed  Google Scholar 

  38. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 2008, 455: 396–400.

    Article  CAS  PubMed  Google Scholar 

  39. Bhattacharya A, Parillon X, Zeng S, Han S, Eissa NT. Deficiency of autophagy in dendritic cells protects against experimental autoimmune encephalomyelitis. J Biol Chem 2014, 289: 26525–26532.

    Article  CAS  PubMed  Google Scholar 

  40. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 2010, 16: 90–97.

    Article  CAS  PubMed  Google Scholar 

  41. Ireland JM, Unanue ER. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J Exp Med 2011, 208: 2625–2632.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Jia W, Pua HH, Li QJ, He YW. Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes. J Immunol 2011, 186: 1564–1574.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Lee JS, Li Q, Lee JY, Lee SH, Jeong JH, Lee HR, et al. FLIPmediated autophagy regulation in cell death control. Nat Cell Biol 2009, 11: 1355–1362.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. He MX, He YW. A role for c-FLIP(L) in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes. Cell Death Differ 2013, 20: 188–197.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Hubbard VM, Valdor R, Patel B, Singh R, Cuervo AM, Macian F. Macroautophagy regulates energy metabolism during effector T cell activation. J Immunol 2010, 185: 7349–7357.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Ni Choileain S, Astier AL. CD46 plasticity and its inflammatory bias in multiple sclerosis. Arch Immunol Ther Exp (Warsz) 2011, 59: 49–59.

    Article  Google Scholar 

  47. Yin L, Liu J, Dong H, Xu E, Qiao Y, Wang L, et al. Autophagyrelated gene16L2, a potential serum biomarker of multiple sclerosis evaluated by bead-based proteomic technology. Neurosci Lett 2014, 562: 34–38.

    Article  CAS  PubMed  Google Scholar 

  48. Miller BC, Zhao Z, Stephenson LM, Cadwell K, Pua HH, Lee HK, et al. The autophagy gene ATG5 plays an essential role in B lymphocyte development. Autophagy 2008, 4: 309–314.

    Article  CAS  PubMed  Google Scholar 

  49. Pua HH, He YW. Maintaining T lymphocyte homeostasis: another duty of autophagy. Autophagy 2007, 3: 266–267.

    Article  CAS  PubMed  Google Scholar 

  50. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 2007, 204: 25–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009, 30: 832–844.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 2012, 12: 325–338.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Alirezaei M, Fox HS, Flynn CT, Moore CS, Hebb AL, Frausto RF, et al. Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis. Autophagy 2009, 5: 152–158.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Esposito M, Ruffini F, Bellone M, Gagliani N, Battaglia M, Martino G, et al. Rapamycin inhibits relapsing experimental autoimmune encephalomyelitis by both effector and regulatory T cells modulation. J Neuroimmunol 2010, 220: 52–63.

    Article  CAS  PubMed  Google Scholar 

  55. Li C, Capan E, Zhao Y, Zhao J, Stolz D, Watkins SC, et al. Autophagy is induced in CD4+ T cells and important for the growth factor-withdrawal cell death. J Immunol 2006, 177: 5163–5168.

    Article  CAS  PubMed  Google Scholar 

  56. Espert L, Denizot M, Grimaldi M, Robert-Hebmann V, Gay B, Varbanov M, et al. Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J Clin Invest 2006, 116: 2161–2172.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Bell BD, Leverrier S, Weist BM, Newton RH, Arechiga AF, Luhrs KA, et al. FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells. Proc Natl Acad Sci U S A 2008, 105: 16677–16682.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004, 304: 1500–1502.

    Article  CAS  PubMed  Google Scholar 

  59. Oreja-Guevara C, Ramos-Cejudo J, Aroeira LS, Chamorro B, Diez- Tejedor E. TH1/TH2 Cytokine profile in relapsingremitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab. BMC Neurol 2012, 12: 95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006, 441: 880–884.

    Article  CAS  PubMed  Google Scholar 

  61. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki- Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006, 441: 885–889.

    Article  CAS  PubMed  Google Scholar 

  62. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammationinduced death. Cell 2009, 137: 47–59.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 2015, 160: 62–73.

    Article  CAS  PubMed  Google Scholar 

  64. Besser MJ, Ganor Y, Levite M. Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL- 10, TNFalpha or both. J Neuroimmunol 2005, 169: 161–171.

    Article  CAS  PubMed  Google Scholar 

  65. Pacheco R, Contreras F, Zouali M. The dopaminergic system in autoimmune diseases. Front Immunol 2014, 5: 117.

    Article  PubMed Central  PubMed  Google Scholar 

  66. Zhou X, Zhou J, Li X, Guo C, Fang T, Chen Z. GSK-3beta inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury. Biochem Biophys Res Commun 2011, 411: 271–275.

    Article  CAS  PubMed  Google Scholar 

  67. Francois A, Terro F, Quellard N, Fernandez B, Chassaing D, Janet T, et al. Impairment of autophagy in the central nervous system during lipopolysaccharide-induced inflammatory stress in mice. Mol Brain 2014, 7: 56.

    Article  PubMed Central  PubMed  Google Scholar 

  68. Qin AP, Liu CF, Qin YY, Hong LZ, Xu M, Yang L, et al. Autophagy was activated in injured astrocytes and mildly decreased cell survival following glucose and oxygen deprivation and focal cerebral ischemia. Autophagy 2010, 6: 738–753.

    Article  CAS  PubMed  Google Scholar 

  69. Wang JY, Xia Q, Chu KT, Pan J, Sun LN, Zeng B, et al. Severe global cerebral ischemia-induced programmed necrosis of hippocampal CA1 neurons in rat is prevented by 3-methyladenine: a widely used inhibitor of autophagy. J Neuropathol Exp Neurol 2011, 70: 314–322.

    Article  CAS  PubMed  Google Scholar 

  70. Yang Z, Zhong L, Zhong S, Xian R, Yuan B. Hypoxia induces microglia autophagy and neural inflammation injury in focal cerebral ischemia model. Exp Mol Pathol 2015, 98: 219–224.

    Article  CAS  PubMed  Google Scholar 

  71. Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 2014, 112: 24–49.

    Article  CAS  PubMed  Google Scholar 

  72. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 2007, 450: 1253–1257.

    Article  CAS  PubMed  Google Scholar 

  73. Benveniste EN. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med (Berl) 1997, 75: 165–173.

    Article  CAS  Google Scholar 

  74. Chastain EM, Duncan DS, Rodgers JM, Miller SD. The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 2011, 1812: 265–274.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Francois A, Terro F, Janet T, Rioux Bilan A, Paccalin M, Page G. Involvement of interleukin-1beta in the autophagic process of microglia: relevance to Alzheimer's disease. J Neuroinflammation 2013, 10: 151.

    Article  PubMed Central  PubMed  Google Scholar 

  76. Dello Russo C, Lisi L, Feinstein DL, Navarra P. mTOR kinase, a key player in the regulation of glial functions: relevance for the therapy of multiple sclerosis. Glia 2013, 61: 301–311.

    Article  Google Scholar 

  77. Dello Russo C, Lisi L, Tringali G, Navarra P. Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol 2009, 78: 1242–1251.

    Article  Google Scholar 

  78. Alirezaei M, Kiosses WB, Flynn CT, Brady NR, Fox HS. Disruption of neuronal autophagy by infected microglia results in neurodegeneration. PLoS One 2008, 3: e2906.

    Article  PubMed Central  PubMed  Google Scholar 

  79. Wang S, Li B, Qiao H, Lv X, Liang Q, Shi Z, et al. Autophagyrelated gene Atg5 is essential for astrocyte differentiation in the developing mouse cortex. EMBO Rep 2014, 15: 1053–1061.

    Article  CAS  PubMed  Google Scholar 

  80. Lee SJ, Cho KS, Koh JY. Oxidative injury triggers autophagy in astrocytes: the role of endogenous zinc. Glia 2009, 57: 1351–1361.

    Article  PubMed  Google Scholar 

  81. Pastor MD, Garcia-Yebenes I, Fradejas N, Perez-Ortiz JM, Mora- Lee S, Tranque P, et al. mTOR/S6 kinase pathway contributes to astrocyte survival during ischemia. J Biol Chem 2009, 284: 22067–22078.

    Article  CAS  PubMed  Google Scholar 

  82. Cross AH, Manning PT, Keeling RM, Schmidt RE, Misko TP. Peroxynitrite formation within the central nervous system in active multiple sclerosis. J Neuroimmunol 1998, 88: 45–56.

    Article  CAS  PubMed  Google Scholar 

  83. Lisi L, Navarra P, Feinstein DL, Dello Russo C. The mTOR kinase inhibitor rapamycin decreases iNOS mRNA stability in astrocytes. J Neuroinflammation 2011, 8: 1.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Sarkar S, Korolchuk VI, Renna M, Imarisio S, Fleming A, Williams A, et al. Complex inhibitory effects of nitric oxide on autophagy. Mol Cell 2011, 43: 19–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Chang A, Nishiyama A, Peterson J, Prineas J, Trapp BD. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci 2000, 20: 6404–6412.

    CAS  PubMed  Google Scholar 

  86. Wolswijk G. Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain 2002, 125: 338–349.

    Article  PubMed  Google Scholar 

  87. Li W, Tang Y, Fan Z, Meng Y, Yang G, Luo J, et al. Autophagy is involved in oligodendroglial precursor-mediated clearance of amyloid peptide. Mol Neurodegener 2013, 8: 27.

    Google Scholar 

  88. Rangaraju S, Verrier JD, Madorsky I, Nicks J, Dunn WA, Jr., Notterpek L. Rapamycin activates autophagy and improves myelination in explant cultures from neuropathic mice. J Neurosci 2010, 30: 11388–11397.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci 2008, 28: 5422–5432.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Smith CM, Mayer JA, Duncan ID. Autophagy promotes oligodendrocyte survival and function following dysmyelination in a long-lived myelin mutant. J Neurosci 2013, 33: 8088–8100.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Andersson A, Covacu R, Sunnemark D, Danilov AI, Dal Bianco A, Khademi M, et al. Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J Leukoc Biol 2008, 84: 1248–1255.

    Article  CAS  PubMed  Google Scholar 

  92. Laudiero LB, Aloe L, Levi-Montalcini R, Buttinelli C, Schilter D, Gillessen S, et al. Multiple sclerosis patients express increased levels of beta-nerve growth factor in cerebrospinal fluid. Neurosci Lett 1992, 147: 9–12.

    Article  CAS  PubMed  Google Scholar 

  93. Florez-McClure ML, Linseman DA, Chu CT, Barker PA, Bouchard RJ, Le SS, et al. The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. J Neurosci 2004, 24: 4498–4509.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Lindberg RL, De Groot CJ, Certa U, Ravid R, Hoffmann F, Kappos L, et al. Multiple sclerosis as a generalized CNS disease—comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS. J Neuroimmunol 2004, 152: 154–167.

    Article  CAS  PubMed  Google Scholar 

  95. Kim SR, Chen X, Oo TF, Kareva T, Yarygina O, Wang C, et al. Dopaminergic pathway reconstruction by Akt/Rhebinduced axon regeneration. Ann Neurol 2011, 70: 110–120.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 2008, 322: 963–966.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Tullman MJ. A review of current and emerging therapeutic strategies in multiple sclerosis. Am J Manag Care 2013, 19: S21–27.

    PubMed  Google Scholar 

  98. Zhang Y, Guo TB, Lu H. Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges. Neurosci Bull 2013, 29: 144–154.

    Article  PubMed  Google Scholar 

  99. Dang S, Xu H, Xu C, Cai W, Li Q, Cheng Y, et al. Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis. Autophagy 2014, 10: 1301–1315.

    Article  PubMed Central  PubMed  Google Scholar 

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  1. Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Peizhou Liang

  2. Center for Translational Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China

    Peizhou Liang & Weidong Le

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Liang, P., Le, W. Role of autophagy in the pathogenesis of multiple sclerosis. Neurosci. Bull. 31, 435–444 (2015). https://doi.org/10.1007/s12264-015-1545-5

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