Item Details

title

The Role of Ubiquitin-Proteasome-Mediated Proteolysis in Long-term Synaptic Plasticity

author

Haynes, Kathryn Alice

abstract

Elucidating mechanisms by which synapses are modified for long-term memory storage is crucial for explaining normal brain function as well as diseases and disorders of the brain. Numerous studies have shown that new gene expression and new protein synthesis are essential for the synaptic changes that give rise to long-term memory. More recent studies indicate that proteolysis by the ubiquitin-proteasome pathway (UPP) plays a critical role in long-term synaptic plasticity, and dysregulation of this pathway is associated with cognitive impairments in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease. Using the cellular model for long-term synaptic plasticity, late-phase long-term potentiation (L-LTP), our work reveals intricate interactions between proteolysis, protein synthesis in the dendrites and gene transcription in the nucleus. Previously, we showed that the early induction phase of L-LTP, which depends on local protein synthesis within dendrites, is enhanced by proteasome inhibition. We also observed that the later maintenance phase of L-LTP, which relies on translation of newly transcribed mRNAs, is blocked when the proteasome is inhibited. We hypothesized that the proteasome must be regulating both phases of L-LTP by controlling translation within dendrites and transcription within the nucleus. Supporting this hypothesis, we found two translational activators that increase early in L-LTP and two translational repressors that buildup later in L-LTP. Inhibition of the proteasome prior to L-LTP resulted in significant increases in expression of both translation activators and repressors, suggesting that this temporal regulation of translation might contribute to the proteasome’s role in the regulation of L-LTP induction and maintenance. In addition, proteasome inhibition prior to LTP induction significantly increases overall protein synthesis and initially slows protein degradation. Interestingly, we also found that amyloid –β (Aβ) drastically decreases basal and activity-dependent protein synthesis, while proteasome inhibition prior to Aβ treatment rescues this decrease back to control and LTP levels, respectively. Finally, taking a step away from translation and investigating the role of the proteasome in transcriptional regulation, we found that a transcriptional repressor, ATF4, is phosphorylated and degraded early in LTP, indicating a potential critical role for the proteasome in relieving repression of transcription during memory consolidation. These findings shed light on the proteasome-dependent mechanisms behind gene and protein expression in synaptic plasticity and could aide in finding novel therapeutic targets and biomarkers for ameliorating memory impairments in neurodegenerative diseases.

subject

Hippocampus

Memory

Proteasome

Protein Degradation

Synaptic Plasticity

Ubiquitin

contributor

Hegde, Ashok N (committee chair)

Hampson, Robert (committee member)

Oppenheim, Ronald (committee member)

Tytell, Michael (committee member)

date

2015-06-23T08:35:54Z (accessioned)

2017-06-22T08:30:09Z (available)

2015 (issued)

degree

Neurobiology & Anatomy (discipline)

embargo

2017-06-22 (terms)

identifier

http://hdl.handle.net/10339/57156 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation