Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases.
Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases.
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DOI：
10.1016/j.nbd.2017.04.010
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发表时间：
2017-09
影响因子：
6.1
通讯作者：
Morfini GA
中科院分区：
文献类型：
--
作者：
Brady ST;Morfini GA
在各种不相关的成人发病神经退行性疾病（aond）中受到影响的神经元通常表现出“死后”的退行性变模式，其特征是突触功能和神经病变的早期缺陷，早在神经元细胞死亡之前。与这一观察结果一致的是，包括阿尔茨海默病、帕金森病、亨廷顿病和几种运动神经元疾病在内的多种不相关的ads，其特征是与轴突运输（AT）缺陷相关的基于激酶的信号通路的早期改变，AT是一个复杂的细胞过程，涉及基于微管的运动蛋白驱动的多个细胞内运输事件。这些致病事件具有重要的治疗意义，表明关注神经元连接的保存可能比处理神经元细胞死亡更有效地治疗ads。虽然仍在分析aond中AT异常的分子机制，但已积累的证据表明，这些机制与多种aond的病理标志有关：神经元蛋白磷酸化模式的改变。在这里，我们简要概述了AT的主要运动蛋白的生化异质性，它们受到蛋白激酶的调节，以及揭示细胞类型特异性AT特化的证据。当综合考虑时，这些发现可能有助于解释在每种AOND的背景下，独立的致病途径如何对AT产生不同的影响。
Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a “dying back” pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins. These pathogenic events have important therapeutic implications, suggesting that a focus on preservation of neuronal connections may be more effective to treat AONDs than addressing neuronal cell death. While the molecular mechanisms underlying AT abnormalities in AONDs are still being analyzed, evidence has accumulated linking those to a well-established pathological hallmark of multiple AONDs: altered patterns of neuronal protein phosphorylation. Here, we present a short overview on the biochemical heterogeneity of major motor proteins for AT, their regulation by protein kinases, and evidence revealing cell type-specific AT specializations. When considered together, these findings may help explain how independent pathogenic pathways can affect AT differentially in the context of each AOND.
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影响因子：
5.1
作者：
Brady, Scott;Morfini, Gerardo
通讯作者：
Morfini, Gerardo
影响因子：
25
作者：
Bosco, Daryl A.;Morfini, Gerardo;Karabacak, N. Murat;Song, Yuyu;Gros-Louis, Francois;Pasinelli, Piera;Goolsby, Holly;Fontaine, Benjamin A.;Lemay, Nathan;McKenna-Yasek, Diane;Frosch, Matthew P.;Agar, Jeffrey N.;Julien, Jean-Pierre;Brady, Scott T.;Brown, Robert H., Jr.
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作者：
Brill, LB;Pfister, KK
通讯作者：
Pfister, KK
影响因子：
6.1
作者：
Borchelt, DR;Wong, PC;Hoffman, PN
通讯作者：
Hoffman, PN
影响因子：
25
作者：
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通讯作者：
Greengard, Paul