title: Differential effects of Usp14 and Uch-L1 on the ubiquitin proteasome system and synaptic activity.
abstract: The ubiquitin proteasome pathway has been implicated in the pathogenesis of many neurodegenerative diseases, and alterations in two different deubiquitinating enzymes, Uch-L1 and Usp14, result in neurological phenotypes in mice. We identified a new mutation in Uch-L1 and compared the roles of Uch-L1 and Usp14 in the ubiquitin proteasome system. Deficiencies in either Uch-L1 or Usp14 result in decreased levels of ubiquitin, suggesting that they both regulate ubiquitin stability in the nervous system. However, the effect of ubiquitin depletion on viability and onset of symptoms is more severe in the Usp14-deficient mice, and changes in hippocampal synaptic transmission were only observed in Usp14-deficient mice. In addition, while Usp14 appears to function at the proteasome, Uch-L1 deficiency resulted in up-regulation of lysosomal components, indicating that Uch-L1 and Usp14 may differentially affect the ubiquitin proteasome system and synaptic activity by regulating different pools of ubiquitin in the cell.
authors.affiliation: University of Alabama at Birmingham, Department of Neurobiology, Civitan International Research Center, 1825 University Boulevard, Shelby 914, Birmingham, AL 35294, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Walters
authors.forename: S L
authors.initials: SL
authors.lastname: Campbell
authors.forename: P C
authors.initials: PC
authors.lastname: Chen
authors.forename: A P
authors.initials: AP
authors.lastname: Taylor
authors.forename: D G
authors.initials: DG
authors.lastname: Schroeder
authors.forename: L E
authors.initials: LE
authors.lastname: Dobrunz
authors.forename: K
authors.initials: K
authors.lastname: Artavanis-Tsakonas
authors.forename: H L
authors.initials: HL
authors.lastname: Ploegh
authors.forename: J A
authors.initials: JA
authors.lastname: Wilson
authors.forename: G A
authors.initials: GA
authors.lastname: Cox
authors.forename: S M
authors.initials: SM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000033:anatomy & histology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009473:Neuronal Plasticity / Q000502:physiology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; C469268:Usp14 protein, mouse; C496976:Uchl1 protein, mouse
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