Aberrant Protein Synthesis Regulation in Fragile X Mouse Neurons
Kim, Soong Ho
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Permalink
https://hdl.handle.net/2142/82519
Description
Title
Aberrant Protein Synthesis Regulation in Fragile X Mouse Neurons
Author(s)
Kim, Soong Ho
Issue Date
2007
Doctoral Committee Chair(s)
Greenough, William
Department of Study
Neuroscience
Discipline
Neuroscience
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Neuroscience
Language
eng
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.
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