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Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo


In Parkinson’s disease, brain dopamine neurons degenerate most prominently in the substantia nigra1. Neurotrophic factors promote survival, differentiation and maintenance of neurons in developing and adult vertebrate nervous system2,3. The most potent neurotrophic factor for dopamine neurons described so far is the glial-cell-line-derived neurotrophic factor (GDNF)4. Here we have identified a conserved dopamine neurotrophic factor (CDNF) as a trophic factor for dopamine neurons. CDNF, together with its previously described vertebrate and invertebrate homologue the mesencephalic-astrocyte-derived neurotrophic factor5, is a secreted protein with eight conserved cysteine residues, predicting a unique protein fold and defining a new, evolutionarily conserved protein family. CDNF (Armetl1) is expressed in several tissues of mouse and human, including the mouse embryonic and postnatal brain. In vivo, CDNF prevented the 6-hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons in a rat experimental model of Parkinson’s disease. A single injection of CDNF before 6-OHDA delivery into the striatum significantly reduced amphetamine-induced ipsilateral turning behaviour and almost completely rescued dopaminergic tyrosine-hydroxylase-positive cells in the substantia nigra. When administered four weeks after 6-OHDA, intrastriatal injection of CDNF was able to restore the dopaminergic function and prevent the degeneration of dopaminergic neurons in substantia nigra. Thus, CDNF was at least as efficient as GDNF in both experimental settings. Our results suggest that CDNF might be beneficial for the treatment of Parkinson’s disease.

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Figure 1: CDNF is an evolutionarily conserved secreted protein.
Figure 2: Mouse CDNF mRNA and protein are expressed in developing and adult brain and in non-neuronal tissues.
Figure 3: CDNF protects nigral dopaminergic neurons in vivo.
Figure 4: CDNF rescues nigral dopaminergic neurons in vivo.

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  1. Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003)

    Article  CAS  Google Scholar 

  2. Airaksinen, M. S. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nature Rev. Neurosci. 3, 383–394 (2002)

    Article  CAS  Google Scholar 

  3. Huang, E. J. & Reichardt, L. F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001)

    Article  CAS  Google Scholar 

  4. Lin, L. F., Doherty, D. H., Lile, J. D., Bektesh, S. & Collins, F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–1132 (1993)

    Article  ADS  CAS  Google Scholar 

  5. Petrova, P. S. et al. MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J. Mol. Neurosci. 20, 173–187 (2003)

    Article  CAS  Google Scholar 

  6. Gill, S. S. et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nature Med. 9, 589–595 (2003)

    Article  CAS  Google Scholar 

  7. Patel, N. K. et al. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann. Neurol. 57, 298–302 (2005)

    Article  CAS  Google Scholar 

  8. Lang, A. E. et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59, 459–466 (2006)

    Article  CAS  Google Scholar 

  9. Ungerstedt, U. & Arbuthnott, G. W. Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res. 24, 485–493 (1970)

    Article  CAS  Google Scholar 

  10. Kearns, C. M. & Gash, D. M. GDNF protects nigral dopamine neurons against 6-hydroxydopamine in vivo. Brain Res. 672, 104–111 (1995)

    Article  CAS  Google Scholar 

  11. Aoi, M., Date, I., Tomita, S. & Ohmoto, T. The effect of intrastriatal single injection of GDNF on the nigrostriatal dopaminergic system in hemiparkinsonian rats: behavioral and histological studies using two different dosages. Neurosci. Res. 36, 319–325 (2000)

    Article  CAS  Google Scholar 

  12. Kirik, D., Rosenblad, C. & Björklund, A. Preservation of a functional nigrostriatal dopamine pathway by GDNF in the intrastriatal 6-OHDA lesion model depends on the site of administration of the trophic factor. Eur. J. Neurosci. 12, 3871–3882 (2000)

    Article  CAS  Google Scholar 

  13. Åkerud, P., Canals, J. M., Snyder, E. Y. & Arenas, E. Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease. J. Neurosci. 21, 8108–8118 (2001)

    Article  Google Scholar 

  14. Jaaro, H., Beck, G., Conticello, S. G. & Fainzilber, M. Evolving better brains: a need for neurotrophins? Trends Neurosci. 24, 79–85 (2001)

    Article  CAS  Google Scholar 

  15. Hidalgo, A., Learte, A. R., McQuilton, P., Pennack, J. & Zhu, B. Neurotrophic and gliatrophic contexts in Drosophila.. Brain Behav. Evol. 68, 173–180 (2006)

    Article  Google Scholar 

  16. Kramer, E. R. et al. Absence of ret signaling in mice causes progressive and late degeneration of the nigrostriatal system. PLoS Biol. 5, e39 (2007)

    Article  Google Scholar 

  17. Sánchez, M. P. et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382, 70–73 (1996)

    Article  ADS  Google Scholar 

  18. Pichel, J. G. et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382, 73–76 (1996)

    Article  ADS  CAS  Google Scholar 

  19. Moore, M. W. et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 76–79 (1996)

    Article  ADS  CAS  Google Scholar 

  20. Granholm, A. C. et al. Morphological alterations in the peripheral and central nervous systems of mice lacking glial cell line-derived neurotrophic factor (GDNF): immunohistochemical studies. J. Neurosci. 17, 1168–1178 (1997)

    Article  CAS  Google Scholar 

  21. Bowenkamp, K. E. et al. Glial cell line-derived neurotrophic factor supports survival of injured midbrain dopaminergic neurons. J. Comp. Neurol. 355, 479–489 (1995)

    Article  CAS  Google Scholar 

  22. Hoffer, B. J. et al. Glial cell line-derived neurotrophic factor reverses toxin-induced injury to midbrain dopaminergic neurons in vivo. Neurosci. Lett. 182, 107–111 (1994)

    Article  CAS  Google Scholar 

  23. Rosenblad, C., Martinez-Serrano, A. & Björklund, A. Intrastriatal glial cell line-derived neurotrophic factor promotes sprouting of spared nigrostriatal dopaminergic afferents and induces recovery of function in a rat model of Parkinson's disease. Neuroscience 82, 129–137 (1998)

    Article  CAS  Google Scholar 

  24. Rosenblad, C. et al. Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson’s disease after administration into the striatum or the lateral ventricle. Eur. J. Neurosci. 11, 1554–1566 (1999)

    Article  CAS  Google Scholar 

  25. Sauer, H. & Oertel, W. H. Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59, 401–415 (1994)

    Article  CAS  Google Scholar 

  26. Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates. (Academic Press, San Diego, 1997)

  27. Kearns, C. M., Cass, W. A., Smoot, K., Kryscio, R. & Gash, D. M. GDNF protection against 6-OHDA: time dependence and requirement for protein synthesis. J. Neurosci. 17, 7111–7118 (1997)

    Article  CAS  Google Scholar 

  28. Janhunen, S., Tuominen, R. K. & Ahtee, L. Comparison of the effects of nicotine and epibatidine given in combination with nomifensine on rotational behaviour in rats. Neurosci. Lett. 381, 314–319 (2005)

    Article  CAS  Google Scholar 

  29. West, M. J., Slomianka, L. & Gundersen, H. J. Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat. Rec. 231, 482–497 (1991)

    Article  CAS  Google Scholar 

  30. Timmusk, T., Belluardo, N., Metsis, M. & Persson, H. Widespread and developmentally regulated expression of neurotrophin-4 mRNA in rat brain and peripheral tissues. Eur. J. Neurosci. 5, 605–613 (1993)

    Article  CAS  Google Scholar 

  31. Keinänen, K., Jouppila, A. & Kuusinen, A. Characterization of the kainate-binding domain of the glutamate receptor GluR-6 subunit. Biochem. J. 330, 1461–1467 (1998)

    Article  Google Scholar 

  32. Peränen, J., Rikkonen, M., Hyvönen, M. & Kääriäinen, L. T7 vectors with a modified T7lac promoter for expression of proteins in Escherichia coli. Anal. Biochem. 236, 371–373 (1996)

    Article  Google Scholar 

  33. Peränen, J. & Furuhjelm, J. Expression, purification and properties of Rab8 function in actin cortical skeleton organization and polarized transport. Methods Enzymol. 329, 188–196 (2001)

    Article  Google Scholar 

  34. Kirik, D., Georgievska, B., Rosenblad, C. & Björklund, A. Delayed infusion of GDNF promotes recovery of motor function in the partial model of Parkinson’s disease. Eur. J. Neurosci. 13, 1589–1599 (2001)

    Article  CAS  Google Scholar 

  35. Sauer, H., Rosenblad, C. & Björklund, A. Glial cell line-derived neurotrophic factor but not transforming growth factor β3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion. Proc. Natl Acad. Sci. USA 92, 8935–8939 (1995)

    Article  ADS  CAS  Google Scholar 

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We thank U. Arumäe and L.Yu for sharing their expertise on culturing methods of dopaminergic neurons; L.Yu, J.Yang and M. Paveliev for performing assays on superior cervical ganglion and dorsal root ganglion neurons; and E. Jõeste and L. Kiho for help in collecting human brain tissue. We thank O. deLapeyrière, who conducted the experiments on motoneurons. We are grateful to K. Unsicker, who taught us and carried out initial assays with rat dopaminergic neurons. R. Ala-Kulju, M. Heikkinen, A. Hienola, E. Kujamäki, L. Lindgren, M. Lindgren, G. Rönnholm, A. Tiilikka, M. Vaha, K. Valkonen, S. Vasilieva, S. Wiss and S. Åkerberg are thanked for excellent technical assistance. We thank M. S. Airaksinen, U. Arumäe, E. Castrén, T. Heino, B. Hoffer, H. Rauvala, C. Rivera, P. Runeberg-Roos and H. Sariola for critical comments on the manuscript. T.T. is a Wellcome Trust International Senior Research Fellow in Biomedical Science in Central Europe. This work was supported by Sigrid Jusélius Foundation grants for M.S., T.T. and R.K.T. and by the Academy of Finland Neuroscience Programme grant for M.S. R.K.T. and M.S. are supported by the Michael J. Fox Foundation. T.T. was supported by a grant from Estonian Ministry of Education and Research. M.H.V. was supported by a grant from the Helsinki University Pharmacy.

Author Contributions P.L., J.L., T.T. and M.S. discovered the new neurotrophic factor. P.L. expressed and purified the protein, studied its tissue expression and together with M.H.V. and M.S. wrote the paper. M.H.V. planned and carried out the neuroprotection and neurorestoration experiments in vivo. J.P. raised the CDNF antibodies. V.-M.L. helped in CDNF purification and N.K. did the protein sequencing and mass analysis. J.-O.A. and M.L. did in vitro assays with neurons. R.K.T. and S.J. planned and supervised the in vivo experiments and M.S. supervised the whole project. All authors commented on the manuscript.

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Correspondence to Mart Saarma.

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Lindholm, P., Voutilainen, M., Laurén, J. et al. Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature 448, 73–77 (2007).

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