1. Institute of Biotechnology, P.O. Box 56, Viikki Biocenter, University of Helsinki, FIN-00014, Helsinki, Finland
2. Division of Pharmacology and Toxicology, Faculty of Pharmacy, P.O. Box 56,Viikki Biocenter, University of Helsinki, FIN-00014, Helsinki, Finland
3. Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, 19086 Tallinn, Estonia
4. Present addresses: Department of Neurology, Yale University School of Medicine, P.O. Box 208018, New Haven, Connecticut 06520, USA (J.L.); Department of Pharmacology, CARIM, University of Maastricht, P.O. Box 616, Maastricht, 6200 MD, The Netherlands (S.J.).

Correspondence to: Mart Saarma¹ Correspondence and requests for materials should be addressed to M.S. (Email: mart.saarma@helsinki.fi).

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 system^{2, 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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