Coordinate regulation of mature dopaminergic axon morphology by macroautophagy and the PTEN signaling pathway.
Coordinate regulation of mature dopaminergic axon morphology by macroautophagy and the PTEN signaling pathway.
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DOI：
10.1371/journal.pgen.1003845
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Abeliovich A
中科院分区：
文献类型：
--
作者：
Inoue K;Rispoli J;Yang L;Macleod D;Beal MF;Klann E;Abeliovich A
大自噬是蛋白质和细胞器大量降解的保守机制。病理学研究表明，在神经退行性变中存在缺陷的宏自噬，但成年神经元中宏自噬的生理功能尚不清楚。在这里，我们表明，Atg 7，一个必不可少的macroautophagy组件，调节多巴胺能轴突终端形态。成熟的Atg 7缺陷中脑多巴胺（DA）神经元窝藏选择性扩大轴突终末。这与Pten缺陷的DA神经元的表型形成对比，Pten是mTOR激酶信号通路和神经元大小的关键负调节因子，其表现为索马体增大但轴突终末不变。令人惊讶的是，Atg 7和Pten两者的伴随缺陷导致轴突末端扩大相对于单独的Atg 7缺失的显著增强。Atg 7和Pten之间类似的遗传相互作用的情况下，观察DA营业额和DA依赖的运动行为。这些数据表明，成熟的多巴胺能轴突终末的形态调控模型，其中mTOR通路的影响被抑制的宏自噬。巨自噬是细胞中主要的再循环途径，其功能障碍与神经系统疾病相关，包括阿尔茨海默病、帕金森病和额颞叶痴呆。在这里，我们表明，Atg 7，一个重要组成部分的macroautophagy，调节成熟的多巴胺能轴突终端的形态协调与充分描述的作用PI 3 K通路。Pten是PI 3 K/mTOR通路的负调节因子，Pten的缺乏主要导致多巴胺能细胞索马体增大，但轴突终末外观正常，而Atg 7缺乏主要诱导轴突终末增大。Atg 7和Pten双重缺陷导致轴突终末进一步增大，表明Atg 7缺陷揭示了PI 3 K/mTOR通路对成熟多巴胺能轴突终末的影响。此外，我们表明，Atg 7和Pten协调调节纹状体多巴胺营业额和多巴胺依赖的运动行为。总之，这些数据支持Atg 7依赖性巨自噬在调节多巴胺能轴突终末形态中的新作用，与PI 3 K/mTOR通路协调。
Macroautophagy is a conserved mechanism for the bulk degradation of proteins and organelles. Pathological studies have implicated defective macroautophagy in neurodegeneration, but physiological functions of macroautophagy in adult neurons remain unclear. Here we show that Atg7, an essential macroautophagy component, regulates dopaminergic axon terminal morphology. Mature Atg7-deficient midbrain dopamine (DA) neurons harbored selectively enlarged axonal terminals. This contrasted with the phenotype of DA neurons deficient in Pten – a key negative regulator of the mTOR kinase signaling pathway and neuron size – that displayed enlarged soma but unaltered axon terminals. Surprisingly, concomitant deficiency of both Atg7 and Pten led to a dramatic enhancement of axon terminal enlargement relative to Atg7 deletion alone. Similar genetic interactions between Atg7 and Pten were observed in the context of DA turnover and DA-dependent locomotor behaviors. These data suggest a model for morphological regulation of mature dopaminergic axon terminals whereby the impact of mTOR pathway is suppressed by macroautophagy. Macroautophagy is a major recycling pathway in cells, and its dysfunction is associated with neurological disorders including Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. Here we show that Atg7, an essential component of macroautophagy, regulates mature dopaminergic axon terminal morphology in coordination with the well-described role of the PI3K pathway. Deficiency of Pten, a negative regulator of the PI3K/mTOR pathway, leads primarily to enlarged dopaminergic cell soma but normal-appearing axonal terminals, whereas Atg7 deficiency primarily induces enlarged axonal terminals. Atg7 and Pten double deficiency leads to further axon terminal enlargement, suggesting that Atg7 deficiency unmasks the impact of PI3K/mTOR pathway on mature dopaminergic axon terminals. In addition, we show that Atg7 and Pten coordinately regulate striatal dopamine turnover and dopamine-dependent motor behaviors. Taken together, these data support a novel role for Atg7-dependent macroautophagy in the regulation of dopaminergic axon terminal morphology, in coordination with the PI3K/mTOR pathway.
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影响因子：
2.7
作者：
HEDGECOCK, EM;CULOTTI, JG;PERKINS, LA
通讯作者：
PERKINS, LA
影响因子：
10.5
作者：
Chalhoub, Nader;Zhu, Guo;Baker, Suzanne J.
通讯作者：
Baker, Suzanne J.
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T
影响因子：
16.2
作者：
Hernandez D;Torres CA;Setlik W;Cebrián C;Mosharov EV;Tang G;Cheng HC;Kholodilov N;Yarygina O;Burke RE;Gershon M;Sulzer D
通讯作者：
Sulzer D
DOI：
10.1523/jneurosci.0209-12.2012
发表时间：
2012-11-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ahmed I;Liang Y;Schools S;Dawson VL;Dawson TM;Savitt JM
通讯作者：
Savitt JM