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

• Published in: Nature Vol. 448; no. 7149; pp. 73 - 77
• Main Authors: Laurén, Juha, Lindholm, Päivi, Voutilainen, Merja H, Lindahl, Maria, Andressoo, Jaan-Olle, Saarma, Mart, Leppänen, Veli-Matti, Tuominen, Raimo K, Janhunen, Sanna, Timmusk, Tõnis, Peränen, Johan, Kalkkinen, Nisse
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 05.07.2007; Nature Publishing Group
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Biomedical materials; Brain - embryology; Brain - metabolism; Cell physiology; Cloning, Molecular; Conserved Sequence; Corpus Striatum - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine; Dopamine - metabolism; Drug therapy; Fundamental and applied biological sciences. Psychology; Genetic aspects; Humans; In Situ Hybridization; In vivo tests; Injection; Invertebrates; Male; Mathematical models; Medical research; Medical sciences; Medicin och hälsovetenskap; Mice; Molecular and cellular biology; Molecular Sequence Data; Nerve Growth Factors - genetics; Nerve Growth Factors - physiology; Nerve Growth Factors - secretion; Nerve Growth Factors - therapeutic use; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Nervous system; Neurology; Neurons; Neurons - metabolism; Neurons - physiology; Neuroprotective Agents - therapeutic use; Neurotrophic functions; Oxidopamine; Parkinson disease; Parkinson Disease - drug therapy; Parkinson's disease; Physiological aspects; Protein Processing, Post-Translational; Proteins; Rats; Rats, Wistar; Responses to growth factors, tumor promotors, other factors; RNA, Messenger; Substantia Nigra - metabolism; Surgical implants; Vertebrates; Psychotropic; Neuroglia; Central nervous system; Parkinson disease; Encephalon; Development; Glial cell line derived neurotrophic factor; Degenerative disease; Human; Nervous system diseases; Dopamine; CNS stimulant; Rodentia; Trophic factor; Midbrain; Basal ganglion; Astrocyte; Catecholamine; Survival; Neurotrophic factor; Vertebrata; Mammalia; Locus niger; Mouse; Animal; Neurotransmitter; Dopaminergic neuron; Differentiation
• ISSN: 0028-0836; 1476-4687; 1476-4687; 1476-4679
• DOI: 10.1038/nature05957

In Parkinson's disease, brain dopamine neurons degenerate most prominently in the substantia nigra. Neurotrophic factors promote survival, differentiation and maintenance of neurons in developing and adult vertebrate nervous system. The most potent neurotrophic factor for dopamine neurons described so far is the glial-cell-line-derived neurotrophic factor (GDNF). 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 factor, 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.