Advertisement

Neuroscience Bulletin

, Volume 33, Issue 5, pp 568–575 | Cite as

Cerebral Dopamine Neurotrophic Factor: A Potential Therapeutic Agent for Parkinson’s Disease

  • Tingting Tang
  • Yong Li
  • Qian Jiao
  • Xixun Du
  • Hong Jiang
Review

Abstract

The application of neurotrophic factors (NTFs) is a promising therapeutic strategy for neurodegenerative disorders such as Parkinson’s disease (PD). Many NTFs have been reported to enhance the survival, regeneration, and differentiation of neurons and to induce synaptic plasticity. However, because of their potential side-effects and low efficacy after clinical administration, more potent treatments for neurodegenerative disorders are being sought. Cerebral dopamine neurotrophic factor (CDNF), a newly-identified NTF homologous to mesencephalic astrocyte-derived NTF, is structurally and functionally different from other NTFs, providing new hope especially for PD patients. In various animal models of PD, CDNF is efficient in protecting and repairing dopaminergic neurons, and it inhibits endoplasmic reticulum stress, neuroinflammation, and apoptosis. Recent progress in all facets of CDNF research has enabled researchers to better understand its beneficial effects in the treatment of PD.

Keywords

Cerebral dopamine neurotrophic factor Parkinson’s disease Neuroprotection Anti-inflammatory Anti-apoptotic 

Notes

Acknowledgments

This review was supported by the National Natural Science Foundation of China (31471114, 31500837, and 31540075), the Taishan Scholarship and Program for New Century Excellent Talents in University, and the Natural Science Foundation of Shandong Province, China (BS2015SW022).

References

  1. 1.
    Deister C, Schmidt CE. Optimizing neurotrophic factor combinations for neurite outgrowth. J Neural Eng 2006, 3: 172–179.CrossRefPubMedGoogle Scholar
  2. 2.
    Rodrigues TM, Jeronimo-Santos A, Outeiro TF, Sebastiao AM, Diogenes MJ. Challenges and promises in the development of neurotrophic factor-based therapies for Parkinson’s disease. Drugs Aging 2014, 31: 239–261.CrossRefPubMedGoogle Scholar
  3. 3.
    Lindholm P, Voutilainen MH, Lauren J, Peranen J, Leppanen VM, Andressoo JO, et al. Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature 2007, 448: 73–77.CrossRefPubMedGoogle Scholar
  4. 4.
    Petrova P, Raibekas A, Pevsner J, Vigo N, Anafi M, Moore MK, et al. MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci 2003, 20: 173–188.CrossRefPubMedGoogle Scholar
  5. 5.
    Rangasamy SB, Soderstrom K, Bakay RA, Kordower JH. Neurotrophic factor therapy for Parkinson’s disease. Prog Brain Res 2010, 184: 237–264.CrossRefPubMedGoogle Scholar
  6. 6.
    Batla A, Tayim N, Pakzad M, Panicker JN. Treatment options for urogenital dysfunction in Parkinson’s disease. Curr Treat Options Neurol 2016, 18: 45.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Su YR, Wang J, Wu JJ, Chen Y, Jiang YP. Overexpression of lentivirus-mediated glial cell line-derived neurotrophic factor in bone marrow stromal cells and its neuroprotection for the PC12 cells damaged by lactacystin. Neurosci Bull 2007, 23: 67–74.CrossRefPubMedGoogle Scholar
  8. 8.
    Airavaara M, Harvey BK, Voutilainen MH, Shen H, Chou J, Lindholm P, et al. CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice. Cell Transplant 2012, 21: 1213–1223.CrossRefPubMedGoogle Scholar
  9. 9.
    Nadella R, Voutilainen MH, Saarma M, Gonzalez-Barrios JA, Leon-Chavez BA, Jimenez JM, et al. Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra. J Neuroinflammation 2014, 11: 209.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Latge C, Cabral KM, de Oliveira GA, Raymundo DP, Freitas JA, Johanson L, et al. The solution structure and dynamics of full-length human cerebral dopamine neurotrophic factor and its neuroprotective role against alpha-synuclein oligomers. J Biol Chem 2015, 290: 20527–20540.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Back S, Peranen J, Galli E, Pulkkila P, Lonka-Nevalaita L, Tamminen T, et al. Gene therapy with AAV2-CDNF provides functional benefits in a rat model of Parkinson’s disease. Brain Behav 2013, 3: 75–88.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Parkash V, Lindholm P, Peranen J, Kalkkinen N, Oksanen E, Saarma M, et al. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein Eng Des Sel 2009, 22: 233–241.CrossRefPubMedGoogle Scholar
  13. 13.
    Hellman M, Arumae U, Yu LY, Lindholm P, Peranen J, Saarma M, et al. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. J Biol Chem 2011, 286: 2675–2680.CrossRefPubMedGoogle Scholar
  14. 14.
    Vimal P, PäIvi L, Johan PN, Nisse K, Esko O, Mart S, et al. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein Eng Des Sel 2009, 22: 233–241.CrossRefGoogle Scholar
  15. 15.
    Lindahl M, Saarma M, Lindholm P. Unconventional neurotrophic factors CDNF and MANF: Structure, physiological functions and therapeutic potential. Neurobiol Dis 2017, 97: 90–102.CrossRefPubMedGoogle Scholar
  16. 16.
    Lohoff FW, Bloch PJ, Ferraro TN, Berrettini WH, Pettinati HM, Dackis CA, et al. Association analysis between polymorphisms in the conserved dopamine neurotrophic factor (CDNF) gene and cocaine dependence. Neurosci Lett 2009, 453: 199–203.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Apostolou A, Shen Y, Liang Y, Luo J, Fang S. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp Cell Res 2008, 314: 2454–2467.CrossRefPubMedGoogle Scholar
  18. 18.
    Holtz WA, O'Malley KL. Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. J Biol Chem 2003, 278: 19367–19377.CrossRefPubMedGoogle Scholar
  19. 19.
    Gang C, Bower KA, Cuiling M, Shengyun F, Thiele CJ, Jia L. Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. FASEB J 2004, 18: 1162–1164.Google Scholar
  20. 20.
    Yusuke S, Kohsuke T, Hidenori I. The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr Mol Med 2006, 6: 87–97.CrossRefGoogle Scholar
  21. 21.
    Lindholm P, Saarma M. Novel CDNF/MANF family of neurotrophic factors. Dev Neurobiol 2010, 70: 360–371.PubMedGoogle Scholar
  22. 22.
    Lindstrom R, Lindholm P, Kallijarvi J, Yu LY, Piepponen TP, Arumae U, et al. Characterization of the structural and functional determinants of MANF/CDNF in Drosophila in vivo model. PLoS One 2013, 8: e73928.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Liu H, Zhao C, Zhong L, Liu J, Zhang S, Cheng B, et al. Key subdomains in the C-terminal of cerebral dopamine neurotrophic factor regulate the protein secretion. Biochem Biophys Res Commun 2015, 465: 427–432.CrossRefPubMedGoogle Scholar
  24. 24.
    Choi JM, Hong JH, Chae MJ, Ngyuen PH, Kang HS, Ma HI, et al. Analysis of mutations and the association between polymorphisms in the cerebral dopamine neurotrophic factor (CDNF) gene and Parkinson disease. Neurosci Lett 2011, 493: 97–101.CrossRefPubMedGoogle Scholar
  25. 25.
    Sun ZP, Gong L, Huang SH, Geng Z, Cheng L, Chen ZY. Intracellular trafficking and secretion of cerebral dopamine neurotrophic factor in neurosecretory cells. J Neurochem 2011, 117: 121–132.CrossRefPubMedGoogle Scholar
  26. 26.
    Palgi M, Lindstrom R, Peranen J, Piepponen TP, Saarma M, Heino TI. Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons. Proc Natl Acad Sci U S A 2009, 106: 2429–2434.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Niles LP, Sathiyapalan A, Bahna S, Kang NH, Pan Y. Valproic acid up-regulates melatonin MT1 and MT2 receptors and neurotrophic factors CDNF and MANF in the rat brain. Int J Neuropsychopharmacol 2012, 15: 1343–1350.CrossRefPubMedGoogle Scholar
  28. 28.
    Almutawaa W, Kang NH, Pan Y, Niles LP. Induction of neurotrophic and differentiation factors in neural stem cells by valproic acid. Basic Clin Pharmacol Toxicol 2014, 115: 216–221.CrossRefPubMedGoogle Scholar
  29. 29.
    Lindholm P, Peranen J, Andressoo JO, Kalkkinen N, Kokaia Z, Lindvall O, et al. MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Mol Cell Neurosci 2008, 39: 356–371.CrossRefPubMedGoogle Scholar
  30. 30.
    Wang H, Ke Z, Alimov A, Xu M, Frank JA, Fang S, et al. Spatiotemporal expression of MANF in the developing rat brain. PLoS One 2014, 9: e90433.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Tsybko AS, Ilchibaeva TV, Kulikov AV, Kulikova EA, Krasnov IB, Sychev VN, et al. Effect of microgravity on glial cell line-derived neurotrophic factor and cerebral dopamine neurotrophic factor gene expression in the mouse brain. J Neurosci Res 2015, 93: 1399–1404.CrossRefPubMedGoogle Scholar
  32. 32.
    Tadimalla A, Belmont PJ, Thuerauf DJ, Glassy MS, Martindale JJ, Gude N, et al. Mesencephalic astrocyte-derived neurotrophic factor is an ischemia-inducible secreted endoplasmic reticulum stress response protein in the heart. Circ Res 2008, 103: 1249–1258.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Norisada J, Hirata Y, Amaya F, Kiuchi K, Oh-hashi K. A comparative analysis of the molecular features of MANF and CDNF. PLoS One 2016, 11: e0146923.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Glembotski CC, Thuerauf DJ, Huang C, Vekich JA, Gottlieb RA, Doroudgar S. Mesencephalic astrocyte-derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco/endoplasmic reticulum calcium depletion. J Biol Chem 2012, 287: 25893–25904.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lu B. Pro-region of neurotrophins: role in synaptic modulation. Neuron 2003, 39: 735–738.CrossRefPubMedGoogle Scholar
  36. 36.
    Huang J, Chen C, Gu H, Li C, Fu X, Jiang M, et al. Mesencephalic astrocyte-derived neurotrophic factor reduces cell apoptosis via upregulating GRP78 in SH-SY5Y cells. Cell Biol Int 2016, 40: 803–811.CrossRefPubMedGoogle Scholar
  37. 37.
    Chen L, Feng L, Wang X, Du J, Chen Y, Yang W, et al. Mesencephalic astrocyte-derived neurotrophic factor is involved in inflammation by negatively regulating the NF-kappaB pathway. Sci Rep 2015, 5: 8133.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Zhou C, Xiao C, Commissiong JW, Krnjevic K, Ye JH. Mesencephalic astrocyte-derived neurotrophic factor enhances nigral gamma-aminobutyric acid release. Neuroreport 2006, 17: 293–297.CrossRefPubMedGoogle Scholar
  39. 39.
    Voutilainen MH, Back S, Peranen J, Lindholm P, Raasmaja A, Mannisto PT, et al. Chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson’s disease. Exp Neurol 2011, 228: 99–108.CrossRefPubMedGoogle Scholar
  40. 40.
    Kemppainen S, Lindholm P, Galli E, Lahtinen HM, Koivisto H, Hamalainen E, et al. Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer’s disease as well as in wild-type mice. Behav Brain Res 2015, 291: 1–11.CrossRefPubMedGoogle Scholar
  41. 41.
    Zhou W, Chang L, Fang Y, Du Z, Li Y, Song Y, et al. Cerebral dopamine neurotrophic factor alleviates Abeta25-35-induced endoplasmic reticulum stress and early synaptotoxicity in rat hippocampal cells. Neurosci Lett 2016, 633: 40–46.CrossRefPubMedGoogle Scholar
  42. 42.
    Ma CH, Omura T, Cobos EJ, Latremoliere A, Ghasemlou N, Brenner GJ, et al. Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice. J Clin Invest 2011, 121: 4332–4347.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Shakhbazau A, Martinez JA, Xu QG, Kawasoe J, van Minnen J, Midha R. Evidence for a systemic regulation of neurotrophin synthesis in response to peripheral nerve injury. J Neurochem 2012, 122: 501–511.CrossRefPubMedGoogle Scholar
  44. 44.
    Fernández A, Guzmán S, Cruz Y, Zamorano P. Construction of bicistronic lentiviral vectors for tracking the expression of CDNF in transduced cells. Plasmid 2014, 76c: 15–23.Google Scholar
  45. 45.
    Yi L, Lin N, Hua Z, Wen Z, Yuan-Qiang Z, Shuai-Shuai W, et al. Conserved dopamine neurotrophic factor-transduced mesenchymal stem cells promote axon regeneration and functional recovery of injured sciatic nerve. Plos One 2014, 9: e110993–e110993.CrossRefGoogle Scholar
  46. 46.
    Cheng L, Liu Y, Zhao H, Zhang W, Guo YJ, Nie L. Lentiviral-mediated transfer of CDNF promotes nerve regeneration and functional recovery after sciatic nerve injury in adult rats. Biochem Biophys Res Commun 2013, 440: 330–335.CrossRefPubMedGoogle Scholar
  47. 47.
    Garea-Rodriguez E, Eesmaa A, Lindholm P, Schlumbohm C, Konig J, Meller B, et al. Comparative analysis of the effects of neurotrophic factors CDNF and GDNF in a nonhuman primate model of Parkinson’s disease. PLoS One 2016, 11: e0149776.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Walker Z, Costa DC, Walker RW, Lee L, Livingston G, Jaros E, et al. Striatal dopamine transporter in dementia with Lewy bodies and Parkinson disease: a comparison. Neurology 2004, 62: 1568–1572.CrossRefPubMedGoogle Scholar
  49. 49.
    Recasens A, Dehay B, Bove J, Carballo-Carbajal I, Dovero S, Perez-Villalba A, et al. Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014, 75: 351–362.CrossRefPubMedGoogle Scholar
  50. 50.
    Hoffer BJ. Commentary on chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson’s disease. Merja H. Voutilainen et al. Exp Neurol 2011, 230: 162–166.CrossRefPubMedGoogle Scholar
  51. 51.
    Domanskyi A, Saarma M, Airavaara M. Prospects of neurotrophic factors for Parkinson’s disease: comparison of protein and gene therapy. Hum Gene Ther 2015, 26: 550–559.CrossRefPubMedGoogle Scholar
  52. 52.
    Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol 2007, 82: 1083–1094.CrossRefPubMedGoogle Scholar
  53. 53.
    Bohn MC. Motoneurons crave glial cell line-derived neurotrophic factor. Exp Neurol 2004, 190: 263–275.CrossRefPubMedGoogle Scholar
  54. 54.
    Tomac A, Widenfalk J, Lin LF, Kohno T, Ebendal T, Hoffer BJ, et al. Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult. Proc Natl Acad Sci U S A 1995, 92: 8274–8278.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Rocha SM, Cristovao AC, Campos FL, Fonseca CP, Baltazar G. Astrocyte-derived GDNF is a potent inhibitor of microglial activation. Neurobiol Dis 2012, 47: 407–415.CrossRefPubMedGoogle Scholar
  56. 56.
    Cheng L, Zhao H, Zhang W, Liu B, Liu Y, Guo Y, et al. Overexpression of conserved dopamine neurotrophic factor (CDNF) in astrocytes alleviates endoplasmic reticulum stress-induced cell damage and inflammatory cytokine secretion. Biochem Biophys Res Commun 2013, 435: 34–39.CrossRefPubMedGoogle Scholar
  57. 57.
    Zhao H, Cheng L, Liu Y, Zhang W, Maharjan S, Cui Z, et al. Mechanisms of anti-inflammatory property of conserved dopamine neurotrophic factor: inhibition of JNK signaling in lipopolysaccharide-induced microglia. J Mol Neurosci 2014, 52: 186–192.CrossRefPubMedGoogle Scholar
  58. 58.
    Radi E, Formichi P, Battisti C, Federico A. Apoptosis and oxidative stress in neurodegenerative diseases. J Alzheimers Dis 2014, 42 Suppl 3: S125–152.PubMedGoogle Scholar
  59. 59.
    Hosoi T, Ozawa K. Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities. Clin Sci (Lond) 2010, 118: 19–29.CrossRefGoogle Scholar
  60. 60.
    Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, David R, Greene LA. Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J Neurosci 2002, 22: 10690–10698.PubMedGoogle Scholar
  61. 61.
    Lindholm D, Wootz H, Korhonen L. ER stress and neurodegenerative diseases. Cell Death Differ 2006, 13: 385–392.CrossRefPubMedGoogle Scholar
  62. 62.
    Liu H, Tang X, Gong L. Mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor: New endoplasmic reticulum stress response proteins. Eur J Pharmacol 2015, 750: 118–122.CrossRefPubMedGoogle Scholar
  63. 63.
    Mei JM, Niu CS. Effects of CDNF on 6-OHDA-induced apoptosis in PC12 cells via modulation of Bcl-2/Bax and caspase-3 activation. Neurol Sci 2014, 35: 1275–1280.CrossRefPubMedGoogle Scholar
  64. 64.
    Mei J, Niu C. Protective and reversal effects of conserved dopamine neurotrophic factor on PC12 cells following 6-hydroxydopamine administration. Mol Med Rep 2015, 12: 297–302.CrossRefPubMedGoogle Scholar
  65. 65.
    Sawada M, Sun W, Hayes P, Leskov K, Boothman DA, Matsuyama S. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol 2003, 5: 320–329.CrossRefPubMedGoogle Scholar
  66. 66.
    Xu H, Belkacemi L, Jog M, Parrent A, Hebb MO. Neurotrophic factor expression in expandable cell populations from brain samples in living patients with Parkinson’s disease. FASEB J 2013, 27: 4157–4168.CrossRefPubMedGoogle Scholar
  67. 67.
    Mei J, Niu C. Effects of engineered conserved dopamine neurotrophic factor-expressing bone marrow stromal cells on dopaminergic neurons following 6-OHDA administrations. Mol Med Rep 2015, 11: 1207–1213.CrossRefPubMedGoogle Scholar
  68. 68.
    Jiaming M, Niu C. Comparing neuroprotective effects of CDNF-expressing bone marrow derived mesenchymal stem cells via differing routes of administration utilizing an in vivo model of Parkinson’s disease. Neurol Sci 2015, 36: 281–287.CrossRefPubMedGoogle Scholar
  69. 69.
    Zhao H, Cheng L, Du X, Hou Y, Liu Y, Cui Z, et al. Transplantation of cerebral dopamine neurotrophic factor transducted BMSCs in contusion spinal cord injury of rats: promotion of nerve regeneration by alleviating neuroinflammation. Mol Neurobiol 2016, 53: 187–199.CrossRefPubMedGoogle Scholar
  70. 70.
    Bartus RT, Baumann TL, Brown L, Kruegel BR, Ostrove JM, Herzog CD. Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating “clinical proof-of-concept” for AAV-neurturin (CERE-120) in Parkinson’s disease. Neurobiol Aging 2013, 34: 35–61.CrossRefPubMedGoogle Scholar
  71. 71.
    Lim ST, Airavaara M, Harvey BK. Viral vectors for neurotrophic factor delivery: a gene therapy approach for neurodegenerative diseases of the CNS. Pharmacol Res 2010, 61: 14–26.CrossRefPubMedGoogle Scholar
  72. 72.
    Ren X, Zhang T, Gong X, Hu G, Ding W, Wang X. AAV2-mediated striatum delivery of human CDNF prevents the deterioration of midbrain dopamine neurons in a 6-hydroxydopamine induced parkinsonian rat model. Exp Neurol 2013, 248: 148–156.CrossRefPubMedGoogle Scholar
  73. 73.
    Fernandez A, Guzman S, Cruz Y, Zamorano P. Construction of bicistronic lentiviral vectors for tracking the expression of CDNF in transduced cells. Plasmid 2014, 76: 15–23.CrossRefPubMedGoogle Scholar
  74. 74.
    Cordero-Llana O, Houghton BC, Rinaldi F, Taylor H, Yanez-Munoz RJ, Uney JB, et al. Enhanced efficacy of the CDNF/MANF family by combined intranigral overexpression in the 6-OHDA rat model of Parkinson’s disease. Mol Ther 2015, 23: 244–254.CrossRefPubMedGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Science+Business Media Singapore 2017

Authors and Affiliations

  • Tingting Tang
    • 1
  • Yong Li
    • 1
  • Qian Jiao
    • 1
  • Xixun Du
    • 1
  • Hong Jiang
    • 1
  1. 1.Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, State Key Disciplines: PhysiologyMedical College of Qingdao UniversityQingdaoChina

Personalised recommendations