title: Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling.
abstract: 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.
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200231, China.
authors: Zhi-Dong
authors: ZD
authors: Liu
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200231, China.|University of Chinese Academy of Sciences, Beijing, 100049, China.
authors: Su
authors: S
authors: Zhang
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200231, China.
authors: Jian-Jin
authors: JJ
authors: Hao
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200231, China.
authors: Tao-Rong
authors: TR
authors: Xie
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200231, China. jskang@sibs.ac.cn.|University of Chinese Academy of Sciences, Beijing, 100049, China. jskang@sibs.ac.cn.
authors: Jian-Sheng
authors: 0000-0002-2603-9718
authors: JS
authors: Kang
mesh_terms: D000818:Animals; D002460:Cell Line; D056445:Cytoplasmic Dyneins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; C424131:DYNC1LI1 protein, human; C486041:Dync1li1 protein, mouse; D056445:Cytoplasmic Dyneins; D018631:ras Proteins
keywords: RAS-RAF-MEK pathway; atrophy; autophagy; dynein intermediate chain; hippocampal neuron; mitochondria