Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice.
Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice.
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DOI：
10.1016/j.nbd.2010.07.010
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发表时间：
2010-12
影响因子：
6.1
通讯作者：
Farrer MJ
中科院分区：
文献类型：
--
作者：
Melrose HL;Dächsel JC;Behrouz B;Lincoln SJ;Yue M;Hinkle KM;Kent CB;Korvatska E;Taylor JP;Witten L;Liang YQ;Beevers JE;Boules M;Dugger BN;Serna VA;Gaukhman A;Yu X;Castanedes-Casey M;Braithwaite AT;Ogholikhan S;Yu N;Bass D;Tyndall G;Schellenberg GD;Dickson DW;Janus C;Farrer MJ
2004年首次描述的富含亮氨酸重复激酶2（LRRK2）基因突变现已成为常染色体显性遗传和散发性帕金森病（PD）中最重要的遗传学发现。虽然自最初的基因发现以来，人们进行了大量的研究工作，但人们对LRRK 2的正常或病理作用知之甚少。我们已经创建了通过细菌人工染色体（BAC）转基因表达人突变野生型（hWT）或G2019S Lrrk2的小鼠品系。多巴胺能系统的体内分析揭示了在hWT和G2019S转基因小鼠中异常的多巴胺神经传递，其通过细胞外多巴胺水平的降低来证明，这在没有药理学操作的情况下被检测到。免疫病理学分析显示G2019S小鼠中微管结合蛋白tau的定位变化和磷酸化增加。定量生物化学分析证实了G2019S小鼠中存在差异磷酸化tau种类，但令人惊讶的是，在去磷酸化后，G2019S小鼠中的tau同种型带型仍然改变。这表明tau蛋白的其他翻译后修饰发生在G2019S小鼠中。我们假设Lrrk2可能影响tau蛋白的加工，从而导致磷酸化的增加。我们的模型将有助于进一步了解LRRK2的机制作用和未来的治疗筛选。
Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene, first described in 2004 have now emerged as the most important genetic finding in both autosomal dominant and sporadic Parkinson’s Disease (PD). While a formidable research effort has ensued since the initial gene discovery, little is known of either the normal or the pathological role of LRRK2. We have created lines of mice that express human mutant wild-type (hWT) or G2019S Lrrk2 via bacterial artificial chromosome (BAC) transgenesis. In vivo analysis of the dopaminergic system revealed abnormal dopamine neurotransmission in both hWT and G2019S transgenic mice evidenced by a decrease in extra-cellular dopamine levels, which was detected without pharmacological manipulation. Immunopathological analysis revealed changes in localization and increased phosphorylation of microtubule binding protein tau in G2019S mice. Quantitative biochemical analysis confirmed the presence of differential phospho-tau species in G2019S mice but surprisingly, upon dephosphorylation the tau isoform banding pattern in G2019S mice remained altered. This suggests that other post-translational modifications of tau occur in G2019S mice. We hypothesize that Lrrk2 may impact on tau processing which subsequently leads to increased phosphorylation. Our models will be useful for further understanding of the mechanistic actions of LRRK2 and future therapeutic screening.
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影响因子：
4.8
作者：
DREWES, G;TRINCZEK, B;MANDELKOW, E
通讯作者：
MANDELKOW, E
影响因子：
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Cai, Huaibin
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作者：
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Dawson, Valina L.
影响因子：
4.7
作者：
Gillardon, Frank
通讯作者：
Gillardon, Frank
影响因子：
4.2
作者：
Hernández, F;Lucas, JJ;Avila, J
通讯作者：
Avila, J