Dopaminergic expression of the Parkinsonian gene LRRK2-G2019S leads to non-autonomous visual neurodegeneration, accelerated by increased neural demands for energy.
Dopaminergic expression of the Parkinsonian gene LRRK2-G2019S leads to non-autonomous visual neurodegeneration, accelerated by increased neural demands for energy.
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DOI：
10.1093/hmg/ddt061
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发表时间：
2013-06-01
影响因子：
3.5
通讯作者：
Elliott CJ
中科院分区：
文献类型：
--
作者：
Hindle S;Afsari F;Stark M;Middleton CA;Evans GJ;Sweeney ST;Elliott CJ
帕金森氏病(PD)与多巴胺能信号的丧失有关，不仅影响运动，还影响视力。由于哺乳动物和苍蝇的视觉系统都含有多巴胺能神经元，我们研究了LRRK2突变(遗传性帕金森病最常见的原因)对果蝇视网膜电信号(ERGs)的影响。我们揭示了在多巴胺能神经元中表达LRRK2-G2019S的果蝇的光感受器功能的进行性丧失。光感受器表现出自噬、细胞凋亡和线粒体紊乱。头部切片证实了整个视觉系统的广泛神经变性，包括没有直接被多巴胺能神经元神经支配的区域。其他与PD相关的突变不会影响光感受器功能，而且在激酶死亡的转基因患者中也没有发现视力丧失。对果蝇dLRRK水平的操纵表明，G2019S是一个功能获得型突变，而不是显性负突变。视觉系统的活动增加，或者只是多巴胺能神经元的活动增加，加速了G2019S导致的视力下降。苍蝇视觉系统提供了一个很好的，易处理的非自主缺陷模型，让人想起在帕金森病中看到的，并表明增加的能量需求可能有助于LRRK2-G2019S导致神经退化的机制。
Parkinson's disease (PD) is associated with loss of dopaminergic signalling, and affects not just movement, but also vision. As both mammalian and fly visual systems contain dopaminergic neurons, we investigated the effect of LRRK2 mutations (the most common cause of inherited PD) on Drosophila electroretinograms (ERGs). We reveal progressive loss of photoreceptor function in flies expressing LRRK2-G2019S in dopaminergic neurons. The photoreceptors showed elevated autophagy, apoptosis and mitochondrial disorganization. Head sections confirmed extensive neurodegeneration throughout the visual system, including regions not directly innervated by dopaminergic neurons. Other PD-related mutations did not affect photoreceptor function, and no loss of vision was seen with kinase-dead transgenics. Manipulations of the level of Drosophila dLRRK suggest G2019S is acting as a gain-of-function, rather than dominant negative mutation. Increasing activity of the visual system, or of just the dopaminergic neurons, accelerated the G2019S-induced deterioration of vision. The fly visual system provides an excellent, tractable model of a non-autonomous deficit reminiscent of that seen in PD, and suggests that increased energy demand may contribute to the mechanism by which LRRK2-G2019S causes neurodegeneration.
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影响因子：
2.5
作者：
Bishop, Matthew W.;Chakraborty, Subhojit;Ungless, Mark A.
通讯作者：
Ungless, Mark A.
影响因子：
12.4
作者：
Fan, Y.;Bergmann, A.
通讯作者：
Bergmann, A.
DOI：
10.1016/j.bbagen.2004.06.002
发表时间：
2004-09-06
影响因子：
3
作者：
Geng, CX;Pellegrino, A;Pak, WL
通讯作者：
Pak, WL
影响因子：
64.5
作者：
Claridge-Chang A;Roorda RD;Vrontou E;Sjulson L;Li H;Hirsh J;Miesenböck G
通讯作者：
Miesenböck G
影响因子：
2.5
作者：
Hamasaka, Y;Nässel, DR
通讯作者：
Nässel, DR