Disruption of axonal transport perturbs bone morphogenetic protein (BMP)--signaling and contributes to synaptic abnormalities in two neurodegenerative diseases.
Disruption of axonal transport perturbs bone morphogenetic protein (BMP)--signaling and contributes to synaptic abnormalities in two neurodegenerative diseases.
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DOI：
10.1371/journal.pone.0104617
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Gunawardena S
中科院分区：
文献类型：
--
作者：
Kang MJ;Hansen TJ;Mickiewicz M;Kaczynski TJ;Fye S;Gunawardena S
新突触的形成或现有突触的维持需要通过轴突运输将突触组分从索马递送到神经末梢。在果蝇神经肌肉接头（NMJ）的突触形成、维持和功能中重要的一个途径是骨形态发生蛋白（BMP）信号传导途径。在这里，我们表明，轴突运输的扰动直接破坏BMP信号，测量其下游信号，磷酸Mad（p-Mad）。我们发现，BMP途径的组件与驱动蛋白-1和动力蛋白马达蛋白基因相互作用。厚静脉（TKV）囊泡的运动性也受到驱动蛋白-1或动力蛋白马达减少的干扰。有趣的是，动力蛋白突变严重破坏p-Mad信号，而驱动蛋白-1突变体显示p-Mad信号强度轻度降低。类似于BMP途径的组分中的突变体，驱动蛋白-1和动力蛋白运动蛋白突变体也显示突触形态缺陷。引人注目的是，TKV运动性和p-Mad信号传导在表达两种人类疾病蛋白的幼虫中被破坏;谷氨酰胺重复序列（polyQ 77）和具有家族性阿尔茨海默病（AD）突变（APPswe）的人类淀粉样前体蛋白（APP）的扩增。与轴突运输缺陷一致，表达这些疾病蛋白的幼虫显示突触蛋白沿着轴突和突触异常的积累。总之，我们的结果表明，类似于NGF-TrkA信号内体，可能存在直接与分子马达相互作用的BMP信号内体。因此，轴突运输的问题发生在早期，扰乱BMP信号，并可能有助于在这两种疾病中观察到的突触异常。
Formation of new synapses or maintenance of existing synapses requires the delivery of synaptic components from the soma to the nerve termini via axonal transport. One pathway that is important in synapse formation, maintenance and function of the Drosophila neuromuscular junction (NMJ) is the bone morphogenetic protein (BMP)-signaling pathway. Here we show that perturbations in axonal transport directly disrupt BMP signaling, as measured by its downstream signal, phospho Mad (p-Mad). We found that components of the BMP pathway genetically interact with both kinesin-1 and dynein motor proteins. Thick vein (TKV) vesicle motility was also perturbed by reductions in kinesin-1 or dynein motors. Interestingly, dynein mutations severely disrupted p-Mad signaling while kinesin-1 mutants showed a mild reduction in p-Mad signal intensity. Similar to mutants in components of the BMP pathway, both kinesin-1 and dynein motor protein mutants also showed synaptic morphological defects. Strikingly TKV motility and p-Mad signaling were disrupted in larvae expressing two human disease proteins; expansions of glutamine repeats (polyQ77) and human amyloid precursor protein (APP) with a familial Alzheimer's disease (AD) mutation (APPswe). Consistent with axonal transport defects, larvae expressing these disease proteins showed accumulations of synaptic proteins along axons and synaptic abnormalities. Taken together our results suggest that similar to the NGF-TrkA signaling endosome, a BMP signaling endosome that directly interacts with molecular motors likely exist. Thus problems in axonal transport occurs early, perturbs BMP signaling, and likely contributes to the synaptic abnormalities observed in these two diseases.
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影响因子：
4.5
作者：
Füger P;Sreekumar V;Schüle R;Kern JV;Stanchev DT;Schneider CD;Karle KN;Daub KJ;Siegert VK;Flötenmeyer M;Schwarz H;Schöls L;Rasse TM
通讯作者：
Rasse TM
影响因子：
16.2
作者：
DIANTONIO, A;SCHWARZ, TL
通讯作者：
SCHWARZ, TL
影响因子：
56.9
作者：
GHO, M;MCDONALD, K;SAXTON, WM
通讯作者：
SAXTON, WM
影响因子：
16.2
作者：
Fuentes-Medel, Yuly;Budnik, Vivian
通讯作者：
Budnik, Vivian
DOI：
10.1177/1073858408329511
发表时间：
2009-02
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
--
作者：
Cai Q;Sheng ZH
通讯作者：
Sheng ZH