Skip to main content

Advertisement

Log in

Mesencephalic astrocyte-derived neurotrophic factor and its role in nervous system disease

  • Review Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a member of the novel evolutionary conserved neurotrophic factor (NTF) family. MANF has a unique structure and an unparalleled dual mode of action that differs from other known NTFs. Recent studies have shown that MANF protects cells from endoplasmic reticulum stress. In addition, an increasing number of studies have found MANF plays an important role in nervous system disease. This review focuses on MANF, summarizing its unique structure, potential signaling pathway, and role in neurological disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Airavaara M, Harvey BK, Voutilainen MH, Shen H, Chou J, Lindholm P et al (2012) CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice. Cell Transplant 21(6):1213–1223

    Article  PubMed  Google Scholar 

  2. Apostolou A, Shen Y, Liang Y, Luo J, Fang S (2008) Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp Cell Res 314(13):2454–2467

    Article  CAS  PubMed  Google Scholar 

  3. Glembotski CC, Thuerauf DJ, Huang C, Vekich JA, Gottlieb RA, Doroudgar S (2012) Mesencephalic astrocyte-derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco/endoplasmic reticulum calcium depletion. J Biol Chem 287(31):25893–25904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hellman M, Arumae U, Yu LY, Lindholm P, Peranen J, Saarma M et al (2011) Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. J Biol Chem 286(4):2675–2680

    Article  CAS  PubMed  Google Scholar 

  5. Lindholm P, Peranen J, Andressoo JO, Kalkkinen N, Kokaia Z, Lindvall O et al (2008) MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Mol Cell Neurosci 39(3):356–371

    Article  CAS  PubMed  Google Scholar 

  6. Lindholm P, Voutilainen MH, Lauren J, Peranen J, Leppanen VM, Andressoo JO et al (2007) Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature 448(7149):73–77

    Article  CAS  PubMed  Google Scholar 

  7. Voutilainen MH, Back S, Porsti E, Toppinen L, Lindgren L, Lindholm P et al (2009) Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson’s disease. J Neurosci 29(30):9651–9659

    Article  CAS  PubMed  Google Scholar 

  8. Petrova P, Raibekas A, Pevsner J, Vigo N, Anafi M, Moore MK et al (2003) MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci 20(2):173–188

    Article  CAS  PubMed  Google Scholar 

  9. Palgi M, Lindstrom R, Peranen J, Piepponen TP, Saarma M, Heino TI (2009) Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons. Proc Natl Acad Sci U S A 106(7):2429–2434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Palgi M, Greco D, Lindstrom R, Auvinen P, Heino TI (2012) Gene expression analysis of Drosophila MANF mutants reveals perturbations in membrane traffic and major metabolic changes. BMC Genomics 13:134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang H, Ke Z, Alimov A, Xu M, Frank JA, Fang S et al (2014) Spatiotemporal expression of MANF in the developing rat brain. PLoS One 9(2):e90433

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mizobuchi N, Hoseki J, Kubota H, Toyokuni S, Nozaki J-I, Naitoh M et al (2007) ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. Cell Struct Funct 32:41–50

    Article  CAS  PubMed  Google Scholar 

  13. Apostolou A, Shen Y, Liang Y, Luo J, Fang S (2008) Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp Cell Res 314:2454–2467

    Article  CAS  PubMed  Google Scholar 

  14. Tadimalla A, Belmont PJ, Thuerauf DJ, Glassy MS, Martindale JJ, Gude N et al (2008) Mesencephalic astrocyte-derived neurotrophic factor is an ischemia-inducible secreted endoplasmic reticulum stress response protein in the heart. Circ Res 103:1249–1258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Latgé C, Cabral KM, Almeida MS, Foguel D (2013) Foguel (1) H-, (13) C- and (15) N-NMR assignment of the N-terminal domain of human cerebral dopamine neurotrophic factor (CDNF). Biomol NMR Assign 7(1):101–103

    Article  PubMed  Google Scholar 

  16. Latge C, Cabral KM, de Oliveira GA, Raymundo DP, Freitas JA, Johanson L et al (2015) The solution structure and dynamics of full-length human cerebral dopamine neurotrophic factor and its neuroprotective role against alpha-synuclein oligomers. J Biol Chem 290(33):20527–20540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Parkash V, Lindholm P, Peranen J, Kalkkinen N, Oksanen E et al (2009) The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein Eng Des Sel. 22(4):233–241

    Article  CAS  PubMed  Google Scholar 

  18. Lindholm P, Saarma M (2010) Novel CDNF/MANF family of neurotrophic factors. Dev Neurobiol 70:360–371

    CAS  PubMed  Google Scholar 

  19. Parkash V, Lindholm P, Peranen J et al (2009) The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein Eng Des Sel 22(4):233–241

    Article  CAS  PubMed  Google Scholar 

  20. Aravind L, Koonin EV (2000) SAP - a putative DNA-binding motif involved in chromosomal organization. Trends Biochem Sci 25(3):112–114

    Article  CAS  PubMed  Google Scholar 

  21. Hellman M, Arumae U, Yu LY et al (2011) Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. J Biol Chem 286(4):2675–2680

    Article  CAS  PubMed  Google Scholar 

  22. Henderson MJ, Richie CT, Airavaara M et al (2013) Mesence-phalic astrocyte-derived neurotrophic factor (MANF) secretion and cell surface binding are modulated by KDEL receptors. J Biol Chem 288(6):4209–4225

    Article  CAS  PubMed  Google Scholar 

  23. Tadimalla A, Belmont PJ, Thuerauf DJ et al (2008) Mesencephalic astrocyte-derived neurotrophic factor is an ischemia-inducible secreted endoplasmic reticulum stress response protein in the heart. Circ Res 103(11):1249–1258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lin LF, Doherty DH, Lile JD et al (1993) GDNF: a glial cell linederived neurotrophic factor for midbrain dopaminergic neurons. Science 260(5111):1130–1132

    Article  CAS  PubMed  Google Scholar 

  25. Sun ZP, Gong L, Huang SH et al (2011) Intracellular trafficking and secretion of cerebral dopamine neurotrophic factor in neurosecretory cells. J Neurochem 117(1):121–132

    Article  CAS  PubMed  Google Scholar 

  26. Mizobuchi N, Hoseki J, Kubota H et al (2007) ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. J Cell Struct Funct 32(1):41–50

    Article  CAS  Google Scholar 

  27. Higa A, Chevet E (2012) Redox signaling loops in the unfolded protein response. Cell Signal 24(8):1548–1555

    Article  CAS  PubMed  Google Scholar 

  28. Airavaara M, Shen H, Kuo CC et al (2009) Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats. J Comp Neurol 515(1):116–124

    Article  PubMed  PubMed Central  Google Scholar 

  29. Yang W, Shen Y, Chen Y, Chen L, Wang L, Wang H et al (2014) Mesencephalic astrocyte-derived neurotrophic factor prevents neuron loss via inhibiting ischemia-induced apoptosis. J Neurol Sci 344(1–2):129–138

    Article  CAS  PubMed  Google Scholar 

  30. Shen Y, Sun A, Wang Y et al (2012) Upregulation of mesencephalic astrocyte-derived neurotrophic factor in glial cells is associated with ischemia-induced glial activation. J Neuroinflamm 9:254

    Article  CAS  Google Scholar 

  31. Oh-hashi K, Norisada J, Hirata Y, Kiuchi K (2015) Characterization of the role of MANF in regulating the secretion of CRELD2. Biol Pharm Bull 38:722–731

    Article  CAS  PubMed  Google Scholar 

  32. Chen L, Feng L, Wang X, Du J, Chen Y, Yang W et al (2015) Mesencephalic astrocyte-derived neurotrophic factor is involved in inflammation by negatively regulating the NF-kappaB pathway. Sci Rep 5:8133

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhu W, Li J, Liu Y, Xie K, Wang L, Fang J (2016) Mesencephalic astrocyte-derived neurotrophic factor attenuates inflammatory responses in lipopolysaccharide-induced neural stem cells by regulating NF-kappaB and phosphorylation of p38-MAPKs pathways. Immunopharmacol Immunotoxicol 38(3):205–213

    Article  CAS  PubMed  Google Scholar 

  34. Zhang J, Cai Q, Jiang M, Liu Y, Gu H, Guo J et al (2017) Mesencephalic astrocyte-derived neurotrophic factor alleviated 6-OHDA-induced cell damage via ROS-AMPK/mTOR mediated autophagic inhibition [J]. Exp Gerontol 89:45–56

    Article  CAS  PubMed  Google Scholar 

  35. Llewellyn DH, Roderick HL, Rose S (1997) KDEL receptor expression is not coordinatedly up-regulated with ER stress-induced reticuloplasmin expression in HeLa cells. Biochem Biophys Res Commun 240:36–40

    Article  CAS  PubMed  Google Scholar 

  36. Henderson MJ, Richie CT, Airavaara M, Wang Y, Harvey BK (2013) Mesencephalic astrocyte-derived neurotrophic factor (MANF) secretion and cell surface binding are modulated by KDEL receptors. J Biol Chem 288(6):4209–4225

    Article  CAS  PubMed  Google Scholar 

  37. Henderson MJ, Wires ES, Trychta KA, Richie CT, Harvey BK (2014) SERCaMP: a carboxy-terminal protein modification that enables monitoring of ER calcium homeostasis. Mol Biol Cell 25(18):2828–2839

    Article  PubMed  PubMed Central  Google Scholar 

  38. Voutilainen MH, Bäck S, Peränen J et al (2011) Chronic infusion of CDNF prevents 6-OHDA induced deficits in a rat model of Parkinson’s disease. Exp Neurol 228(1):99–108

    Article  CAS  PubMed  Google Scholar 

  39. Huang J, Chen C, Gu H, Li C, Fu X, Jiang M et al (2016) Mesencephalic astrocyte-derived neurotrophic factor reduces cell apoptosis via upregulating GRP78 in SH-SY5Y cells. J Cell Biol Int 40(7):803–811

    Article  CAS  Google Scholar 

  40. Airavaara M, Chiocco MJ, Howard DB, Zuchowski KL, Peranen J, Liu C et al (2010) Widespread cortical expression of MANF by AAV serotype 7: localization and protection against ischemic brain injury. Exp Neurol 225(1):104–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lindstrom R, Lindholm P, Kallijarvi J, Yu LY, Piepponen TP, Arumae U et al (2013) Characterization of the structural and functional determinants of MANF/CDNF in Drosophila in vivo model. PLoS One 8(9):e73928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen YC et al (2012) MANF regulates dopaminergic neuron development in larval zebrafish. Dev Biol 370(2):237–249

    Article  CAS  PubMed  Google Scholar 

  43. Hao F, Yang C, Chen SS, Wang YY, Zhou W, Hao Q et al (2017) Long-term protective effects of AAV9-mesencephalic astrocyte-derived neurotrophic factor gene transfer in parkinsonian rats. J Exp Neurol 291:120–133

    Article  CAS  Google Scholar 

  44. Matlik K, Yu LY, Eesmaa A, Hellman M, Lindholm P, Peranen J, Galli E, Anttila J, Saarma M, Permi P et al (2015) Role of two sequence motifs of mesencephalic astrocyte-derived neurotrophic factor in its survival-promoting activity. Cell Death Dis 6:e2032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang XY, Song MM, Bi SX, Shen YJ, Shen YX, Yu YQ (2016) MRI dynamically evaluates the therapeutic effect of recombinant human MANF on ischemia/reperfusion injury in rats. Int J Mol Sci 17:9

    Google Scholar 

  46. Wang XY, Song MM, Bi SX, Shen YJ, Shen YX, Yu YQ (2016) Chronic restraint stress promotes learning and memory impairment due to enhanced neuronal endoplasmic reticulum stress in the frontal cortex and hippocampus in male mice. Int J Mol Sci 17:9

    Google Scholar 

Download references

Acknowledgements

The authors received no funding for this study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Liu Ling.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Disclosure

Lina Zhu, Deng Chen, Xu Da, Sihan Chen, and Ling Liu have nothing to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li-na, Z., Deng, C., Da, X. et al. Mesencephalic astrocyte-derived neurotrophic factor and its role in nervous system disease. Neurol Sci 38, 1741–1746 (2017). https://doi.org/10.1007/s10072-017-3042-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-017-3042-2

Keywords

Navigation