Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
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DOI：
10.1523/jneurosci.4357-09.2009
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发表时间：
2009-12-16
期刊：
影响因子：
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通讯作者：
Dawson VL
中科院分区：
文献类型：
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作者：
Andres-Mateos E;Mejias R;Sasaki M;Li X;Lin BM;Biskup S;Zhang L;Banerjee R;Thomas B;Yang L;Liu G;Beal MF;Huso DL;Dawson TM;Dawson VL
富含亮氨酸的重复蛋白激酶2(LRRK2)基因的突变是帕金森病(PD)最常见的已知原因。LRRK2功能缺失是否是帕金森病患者多巴胺神经元变性的原因尚不清楚，也不清楚LRRK2激酶活性是否调节了多巴胺能神经元对选择性多巴胺能毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)的敏感性。为了更好地了解LRRK2在DA神经元存活中的作用及其在DA神经元对MPTP易感性中的作用，我们产生了缺乏LRRK2激活域的LRRK2基因敲除(KO)小鼠。在这里，我们展示了LRRK2 KO小鼠是存活的，没有重大的异常，并活到成年。LRRK2KO小鼠的多巴胺能系统是正常的，通过对幼年和老年小鼠的DA神经元数量的体视学评估和对DA及其代谢物的高效液相色谱法进行评估。重要的是，LRRK2KO和野生型(WT)小鼠对MPTP的易感性没有显著差异。这些结果表明，LRRK2在生理条件下对DA神经元的发育和存活几乎没有作用。因此，LRRK2突变引起的帕金森病可能不是由于功能丧失所致。此外，LRRK2不是多巴胺神经元对MPTP敏感性所必需的。
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of Parkinson's disease (PD). Whether loss of LRRK2 function accounts for neurodegeneration of dopamine neurons in PD is not known, nor is it known whether LRRK2 kinase activity modulates the susceptibility of dopamine (DA) neurons to the selective dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). To better understand the role of LRRK2 in DA neuronal survival and its role in the susceptibility of DA neurons to MPTP, we generated LRRK2 knockout (KO) mice lacking the kinase domain of LRRK2. Here we show that LRRK2 KO mice are viable and have no major abnormalities and live to adulthood. The dopaminergic system is normal in LRRK2 KO mice as assessed via HPLC for DA and its metabolites and via stereologic assessment of DA neuron number in young and aged mice. Importantly, there is no significant difference in the susceptibility of LRRK2 KO and wild type (WT) mice to MPTP. These results suggest that LRRK2 plays little if any role in the development and survival of DA neurons under physiologic conditions. Thus, PD due to LRRK2 mutations are likely not due to a loss of function. Moreover, LRRK2 is not required for the susceptibility of DA neurons to MPTP.