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Oncogenic BRAF^(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase

查看全文 作　　者：Qing [1,2]Ye;Pranay [1,3]Srivastava;Nasser Al-[1]Kuwari;Xiqun [1,3]Chen 高影响力作者 机构地区：[1]Department of Neurology,Massachusetts General Hospital,Harvard Medical School,Charlestown,MA,USA;[2]Department of Neurology,Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai,China;[3]Aligning Science Across Parkinson’s(ASAP)Collaborative Research Network,Chevy Chase,MD,USA高影响力机构 出　　处：《Neural Regeneration Research》索引2023年第18卷第7期,共10页高影响力期刊 基　　金：supported by the National Institutes of Health,No. R01NS102735 (to XC);the National Natural Science Foundation of China,No. 82073072 (to XC);the Michael J. Fox Foundation for Parkinson’s Research (MJFF);the Aligning Science Across Parkinson’s Initiative (ASAP),No. ASAP-000312 (to XC) 摘　　要：Activating V600E in v-Raf murine sarcoma viral oncogene homolog B(BRAF)is a common driver mutation in cancers of multiple tissue origins,including melanoma and glioma.BRAF^(V600E) has also been implicated in neurodegeneration.The present study aims to characterize BRAF^(V600E) during cell death and proliferation of three major cell types of the central nervous system:neurons,astrocytes,and microglia.Multiple primary cultures(primary cortical mixed culture)and cell lines of glial cells(BV2)and neurons(SH-SY5Y)were employed.BRAF^(V600E) and BRAF^(WT) expression was mediated by lentivirus or retrovirus.Blockage of downstream effectors(extracellular signal-regulated kinase 1/2 and JNK1/2)were achieved by siRNA.In astrocytes and microglia,BRAF^(V600E) induces cell proliferation,and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase,but not c-Jun N-terminal kinase.Conditioned medium from BRAF^(V600E)-expressing microglia induced neuronal death.In neuronal cells,BRAF^(V600E) directly induces neuronal death,through c-Jun N-terminal kinase but not extracellular signal-regulated kinase.We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease.Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity.It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells. 关 键 词：astrocytes cell death cell proliferation inflammation microglia mutation neurons v-Raf murine sarcoma viral oncogene homolog B(BRAF)
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