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

Abstract

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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Acknowledgements

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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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). https://doi.org/10.1038/nature05957

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