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 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.
Lindholm
Päivi
P
Institute of Biotechnology, P.O. Box 56, Viikki Biocenter, University of Helsinki, FIN-00014, Helsinki, Finland.
Voutilainen
Merja H
MH
Laurén
Juha
J
Peränen
Johan
J
Leppänen
Veli-Matti
VM
Andressoo
Jaan-Olle
JO
Lindahl
Maria
M
Janhunen
Sanna
S
Kalkkinen
Nisse
N
Timmusk
Tõnis
T
Tuominen
Raimo K
RK
Saarma
Mart
M
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D003001:Cloning, Molecular; D017124:Conserved Sequence; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000378:metabolism
C522217:CDNF protein, human; C577430:CDNF protein, rat; C099695:MANF protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C522218:cdnf protein, mouse; D016627:Oxidopamine; D004298:Dopamine