title: Ubiquitin homeostasis is critical for synaptic development and function.
abstract: The ubiquitin-proteasome system (UPS) controls protein abundance and is essential for many aspects of neuronal function. In ataxia (ax(J)) mice, profound neurological and synaptic defects result from a loss-of-function mutation in the proteasome-associated deubiquitinating enzyme Usp14, which is required for recycling ubiquitin from proteasomal substrates. Here, we show that transgenic complementation of ax(J) mice with neuronally expressed ubiquitin prevents early postnatal lethality, restores muscle mass, and corrects developmental and functional deficits resulting from the loss of Usp14, demonstrating that ubiquitin deficiency is a major cause of the neurological defects observed in the ax(J) mice. We also show that proteasome components are normally induced during the first 2 weeks of postnatal development, which coincides with dramatic alterations in polyubiquitin chain formation. These data demonstrate a critical role for ubiquitin homeostasis in synaptic development and function, and show that ubiquitin deficiency may contribute to diseases characterized by synaptic dysfunction.
authors: Department of Neurobiology, Civitan International Research Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors: Ping-Chung
authors: PC
authors: Chen
authors: Bula J
authors: BJ
authors: Bhattacharyya
authors: John
authors: J
authors: Hanna
authors: Heather
authors: H
authors: Minkel
authors: Julie A
authors: JA
authors: Wilson
authors: Daniel
authors: D
authors: Finley
authors: Richard J
authors: RJ
authors: Miller
authors: Scott M
authors: SM
authors: Wilson
mesh_terms: D000818:Animals; D018737:Hand Strength / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D045442:Rotarod Performance Test; D013569:Synapses / Q000502:physiology*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex