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PROTEASOME REGULATES TRANSCRIPTION AND TRANSLATION IN LONG-TERM SYNAPTIC PLASTICITY

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abstract
Long-term synaptic plasticity, which underlies long-term memory, depends on new gene transcription, new protein synthesis, as well as proteolytic degradation of regulatory proteins by the ubiquitin-proteasome pathway (UPP). To study the molecular mechanisms of learning and memory, we use the late phase of long-term potentiation (L-LTP) in the murine hippocampus as a cellular model of long-term synaptic plasticity. Our previous work identified that proteasome inhibition enhances the early, induction part of L-LTP, which depends on local translation of pre-existing mRNAs in the dendrites, and blocks the late, maintenance part of L-LTP, which depends on new gene transcription and translation of newly synthesized mRNAs. The proteasome is also known to have non-proteolytic roles in transcriptional regulation that have never been characterized in the mammalian nervous system. We hypothesized that, depending on its subcellular localization, the proteasome may have different, and even opposite, roles in regulating different phases of L-LTP. In support of our hypothesis, we identified that the proteasome degrades translational activators early, during the induction phase, and translational repressors later, during the maintenance phase, of L-LTP. In addition, proteasome inhibition blocked transcription-promoting epigenetic histone posttranslational modifications (acetylation, methylation and ubiquitination) and inhibited the upregulation of plasticity-related gene, brain-derived neurotrophic factor (Bdnf). Furthermore, we found a novel non-traditional role of proteasomal ATPases in linking L-LTP induction and maintenance phases by activity-dependent cytoplasm-to-nucleus translocation. Our findings shed light on the proteasome-dependent transcription, translation and nucleocytoplasmic signaling in long-term synaptic plasticity. Since dysregulations of the UPP are associated with cognitive impairments in neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s, our work is important for the development of novel therapeutic targets and biomarkers for ameliorating memory impairments in neurodegenerative diseases.
subject
epigenetics
proteasome
synaptic plasticity
transcription
translation
contributor
Bach, Svitlana (author)
Hegde, Ashok N. (committee chair)
McCool, Brian (committee member)
Milligan, Carol (committee member)
Oppenheim, Ronald (committee member)
Riddle, David (committee member)
date
2015-06-23T08:35:35Z (accessioned)
2017-06-22T08:30:10Z (available)
2015 (issued)
degree
Neurobiology & Anatomy (discipline)
embargo
2017-06-22 (terms)
identifier
http://hdl.handle.net/10339/57100 (uri)
language
en (iso)
publisher
Wake Forest University
title
PROTEASOME REGULATES TRANSCRIPTION AND TRANSLATION IN LONG-TERM SYNAPTIC PLASTICITY
type
Dissertation

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