Lindholm Päivi, Voutilainen Merja H, Laurén Juha, Peränen Johan, Leppänen Veli-Matti, Andressoo Jaan-Olle, Lindahl Maria, Janhunen Sanna, Kalkkinen Nisse, Timmusk Tõnis, Tuominen Raimo K, Saarma Mart
Institute of Biotechnology, P.O. Box 56, Viikki Biocenter, University of Helsinki, FIN-00014, Helsinki, Finland.
Nature. 2007 Jul 5;448(7149):73-7. 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.
在帕金森病中，脑多巴胺能神经元在黑质中退化最为显著。神经营养因子可促进发育中和成年脊椎动物神经系统中神经元的存活、分化和维持。迄今为止所描述的对多巴胺能神经元最有效的神经营养因子是胶质细胞源性神经营养因子（GDNF）。在此，我们鉴定出一种保守的多巴胺神经营养因子（CDNF）作为多巴胺能神经元的营养因子。CDNF与其先前描述的脊椎动物和无脊椎动物同源物中脑星形胶质细胞源性神经营养因子一起，是一种具有八个保守半胱氨酸残基的分泌蛋白，预示着一种独特的蛋白质折叠方式，并定义了一个新的、进化上保守的蛋白质家族。CDNF（Armetl1）在小鼠和人类的多个组织中表达，包括小鼠胚胎期和出生后的脑。在体内，CDNF在帕金森病大鼠实验模型中可预防6-羟基多巴胺（6-OHDA）诱导的多巴胺能神经元退化。在向纹状体注射6-OHDA之前单次注射CDNF可显著降低苯丙胺诱导的同侧旋转行为，并几乎完全挽救黑质中多巴胺能酪氨酸羟化酶阳性细胞。在6-OHDA注射四周后给予CDNF，纹状体内注射CDNF能够恢复多巴胺能功能并预防黑质中多巴胺能神经元的退化。因此，在这两种实验情况下，CDNF至少与GDNF一样有效。我们的结果表明，CDNF可能对帕金森病的治疗有益。
