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Characterization of the brain proteasome and its interacting proteins and their regulation by neuronal activity

Citation

Tai, Hwan-Ching (2010) Characterization of the brain proteasome and its interacting proteins and their regulation by neuronal activity. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:12092009-103613738

Abstract

Despite the importance of proteasome-mediated proteolysis in synaptic plasticity, protein quality control, and cell regulation, little is known about proteasome composition and regulation in the brain. This thesis represents the first detailed study of mammalian brain proteasomes. Using a new affinity purification method, 26S proteasomes were isolated from the cytosolic and the synaptic compartments of the rat cortex. The proteins associated with the 26S proteasome were purified and analyzed by tandem mass spectrometry. A total of 30 proteasome-interacting proteins were identified in the brain. Several differences were seen in the spectrum of proteasome-associated proteins in the cytosol and the synaptosome. For example, the proteasome-associated protein ECM29 was found only in the cytosolic 26S proteasome, and the ubiquitin-binding factor TAX1BP1 only in the synaptic 26S proteasome. These findings allowed for further investigations into the interplay between proteasome regulation and synaptic plasticity. Neuronal exposure to the neurotransmitter NMDA caused the degradation of 19S particles, resulting in lower levels of 26S proteasomes. The levels of ubiquitin conjugates also decreased, as did two proteasome-bound ubiquitin ligases, UBE3A/E6-AP and HUWE1/ARF-BP1, both of which have been linked to neurogenetic disorders associated with mental retardation. Thus, in the brain, proteasomes have a characteristic set of associated proteins that may serve as regulators or cofactors. Moreover, the content and pattern of associated proteins can vary with synaptic activity, in a manner likely to influence synaptic plasticity.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:proteasome, proteasome interacting proteins, E3 ubiquitin ligase, UBE3A, synaptic plasticity, chemical LTD, NMDA
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Awards:Tobacco-Related Disease Research Program (TRDRP) Dissertation Award, 2004, 2005
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Schuman, Erin Margaret
Thesis Committee:
  • Dougherty, Dennis A. (chair)
  • Barton, Jacqueline K.
  • Zinn, Kai George
  • Parker, Carl Stevens
Defense Date:28 September 2009
Author Email:tai (AT) caltech.edu
Record Number:CaltechTHESIS:12092009-103613738
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:12092009-103613738
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5430
Collection:CaltechTHESIS
Deposited By: Hwan-Ching Tai
Deposited On:23 Dec 2009 17:00
Last Modified:04 Mar 2013 17:33

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