Westerlund Marie, Ran Caroline, Borgkvist Anders, Sterky Fredrik H, Lindqvist Eva, Lundströmer Karin, Pernold Karin, Brené Stefan, Kallunki Pekka, Fisone Gilberto, Olson Lars, Galter Dagmar
Department of Neuroscience, Karolinska Institutet, Retzius väg 8 B2:4, S-17177 Stockholm, Sweden.
Mol Cell Neurosci. 2008 Dec;39(4):586-91. doi: 10.1016/j.mcn.2008.08.001. Epub 2008 Aug 27.
LRRK2, alpha-synuclein, UCH-L1 and DJ-1 are implicated in the etiology of Parkinson's disease. We show for the first time that increase in striatal alpha-synuclein levels induce increased Lrrk2 mRNA levels while Dj-1 and Uch-L1 are unchanged. We also demonstrate that a mouse strain lacking the dopamine signaling molecule DARPP-32 has significantly reduced levels of both Lrrk2 and alpha-synuclein, while mice carrying a disabling mutation of the DARPP-32 phosphorylation site T34A or lack alpha-synuclein do not show any changes. To test if striatal dopamine depletion influences Lrrk2 or alpha-synuclein expression, we used the neurotoxin 6-hydroxydopamine in rats and MitoPark mice in which there is progressive degeneration of dopamine neurons. Because striatal Lrrk2 and alpha-synuclein levels were not changed by dopamine depletion, we conclude that Lrrk2 and alpha-synuclein mRNA levels are possibly co-regulated, but they are not influenced by striatal dopamine levels.
富含亮氨酸重复激酶2（LRRK2）、α-突触核蛋白、泛素羧基末端水解酶L1（UCH-L1）和DJ-1与帕金森病的病因有关。我们首次发现，纹状体中α-突触核蛋白水平的升高会导致Lrrk2 mRNA水平升高，而DJ-1和UCH-L1则保持不变。我们还证明，缺乏多巴胺信号分子多巴胺和3′,5′-环磷酸腺苷调节的磷蛋白-32（DARPP-32）的小鼠品系中，LRRK2和α-突触核蛋白的水平显著降低，而携带DARPP-32磷酸化位点T34A失活突变或缺乏α-突触核蛋白的小鼠则没有任何变化。为了测试纹状体多巴胺耗竭是否会影响LRRK2或α-突触核蛋白的表达，我们在大鼠和多巴胺神经元进行性退化的线粒体帕金森病（MitoPark）小鼠中使用了神经毒素6-羟基多巴胺。由于多巴胺耗竭并未改变纹状体中LRRK2和α-突触核蛋白的水平，我们得出结论，LRRK2和α-突触核蛋白mRNA水平可能共同调节，但不受纹状体多巴胺水平的影响。
