title: Positive feedback regulation of Akt-FMRP pathway protects neurons from cell death.
abstract: J. Neurochem. (2012) 123, 226-238.
  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.
authors: Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul, Korea.
authors: Se Jin
authors: SJ
authors: Jeon
authors: Seol-Heui
authors: SH
authors: Han
authors: Sung-Il
authors: SI
authors: Yang
authors: Ji Woong
authors: JW
authors: Choi
authors: Kyoung Ja
authors: KJ
authors: Kwon
authors: Seung Hwa
authors: SH
authors: Park
authors: Hahn Young
authors: HY
authors: Kim
authors: Jae Hoon
authors: JH
authors: Cheong
authors: Jong Hoon
authors: JH
authors: Ryu
authors: Kwang Ho
authors: KH
authors: Ko
authors: David G
authors: DG
authors: Wells
authors: Chan Young
authors: CY
authors: Shin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000502:physiology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D051057:Proto-Oncogene Proteins c-akt