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Title:Aberrant Protein Synthesis Regulation in Fragile X Mouse Neurons
Author(s):Kim, Soong Ho
Doctoral Committee Chair(s):William Greenough
Department / Program:Neuroscience
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Biology, Neuroscience
Abstract:Finally, we focused on another possibility that abnormal spine morphology in brain of FXS patients and KO mice might be caused by misregulation of signaling pathways in synapses which control translation and transcription (Section 3). When signaling molecules bind to receptors on neurons, numbers of signaling pathways are activated. We have chosen to study phosphorylation of the extracellular-signal-regulated kinase ERK, which is a point of convergence of several signaling cascades that include products of FMRP cargo mRNAs. We isolated cortical synaptoneurosomes (enriched pre/post synaptic subcellular fraction) from WT and KO mice and studied MARK pathway activation in response to Group I metabotropic glutamate receptor activation. While phospho-ERK level increased in WT after mGluR 1 and 5 stimulation, in fmr-1 KO ERK was rapidly dephosphorylated and the decreased level was maintained at least up to 10 minutes, suggesting that aberrant activation of phosphatases occurs in KO synapses in response to synaptic stimulation. We demonstrated that in KO synapses PP2A was hyperactivated after mGluR1 stimulation and tyrosine phosphatase was misactivated after mGluR5 stimulation, which caused the rapid deactivation of ERK. Blocking of PP2A by okadaic acid could successfully restore normal ERK activation in KO synaptoneurosomes. We propose that hyperactivation of phosphatases in synapses may be a key deficit in FXS which affects synaptic translation, transcription and synaptic receptor regulation.
Issue Date:2007
Description:64 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2007.
Other Identifier(s):(MiAaPQ)AAI3301168
Date Available in IDEALS:2015-09-25
Date Deposited:2007

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