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Positive feedback regulation of Akt‐FMRP pathway protects neurons from cell death
Author(s) -
Jeon Se Jin,
Han SeolHeui,
Yang SungIl,
Choi Ji woong,
Kwon Kyoung Ja,
Park Seung Hwa,
Kim Hahn Young,
Cheong Jae Hoon,
Ryu Jong Hoon,
Ko Kwang Ho,
Wells David G,
Shin Chan Young
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07886.x
Subject(s) - protein kinase b , pi3k/akt/mtor pathway , fmr1 , microbiology and biotechnology , biology , fragile x syndrome , programmed cell death , glutamate receptor , neuroscience , apoptosis , signal transduction , gene , genetics , fragile x , receptor
J. Neurochem. (2012) 123 , 226–238. Abstract Fragile X syndrome (FXS), the most common single genetic cause of mental retardation and autistic spectrum disease, occurs when FMR1 gene is mutated. FMR1 encodes fragile X mental retardation protein (FMRP) which regulates translation of mRNAs playing important roles in the development of neurons as well as formation and maintenance of synapses. To examine whether FMRP regulates cell viability, we induced apoptosis in rat primary cortical neurons with glutamate in vitro and with middle cerebral artery occlusion (MCAO) in striatal neurons in vivo . Both conditions elicited a rapid, but transient FMRP expression in neurons. This up‐regulated FMRP expression was abolished by pre‐treatment with PI3K and Protein Kinase B (Akt) inhibitors: LY294002, Akt inhibitor IV, and VIII. Reduced FMRP expression in vitro or in vivo using small hairpin Fmr1 virus exacerbated cell death by glutamate or MCAO, presumably via hypophosphorylation of Akt and reduced expression of B‐cell lymphoma‐extra large (Bcl‐xL). However, over‐expression of FMRP using enhanced green fluorescent protein (eGFP)‐FMRP constructs alleviated cell death, increased Akt activity, and enhanced Bcl‐xL production. The pro‐survival role of Akt‐dependent up‐regulation of FMRP in glutamate‐stimulated cultured neuron as well as in ischemic brain may have a clinical importance in FXS as well as in neurodegenerative disorders and traumatic brain injury.