Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling

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• 作者：Zhi-Dong Liu ; Su Zhang ; Jian-Jin Hao ; Tao-Rong Xie ; Jian-Sheng Kang
• 关键词：RAS ; RAF ; MEK pathway ; atrophy ; dynein intermediate chain ; mitochondria ; hippocampal neuron ; autophagy
• 刊名：Protein & Cell
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：7
• 期：9
• 页码：638-650
• 全文大小：2,774 KB
• 刊物主题：Biochemistry, general; Protein Science; Cell Biology; Stem Cells; Human Genetics; Developmental Biology;
• 出版者：Springer Berlin Heidelberg
• ISSN：1674-8018
• 卷排序：7

文摘

Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein malfunction and mitochondrial dysfunction contribute to the loss of neuronal architecture; however, less is known about the intracellular signaling pathways that can protect against or delay this pathogenic process. Here, we show that the DYNC1I1 deficiency, a neuron-specific dynein intermediate chain, causes neuronal atrophy in primary hippocampal neurons. With this cellular model, we are able to find that activation of RAS-RAF-MEK signaling protects against neuronal atrophy induced by DYNC1I1 deficiency, which relies on MEK-dependent autophagy in neuron. Moreover, we further reveal that BRAF also protects against neuronal atrophy induced by mitochondrial impairment. These findings demonstrate protective roles of the RAS-RAF-MEK axis against neuronal atrophy, and imply a new therapeutic target for clinical intervention.