title: Transgenic rescue of ataxia mice with neuronal-specific expression of ubiquitin-specific protease 14.
abstract: The ataxia mutation (axJ) is a recessive neurological mutation that results in reduced growth, ataxia, and hindlimb muscle wasting in mice. The axJ gene encodes ubiquitin-specific protease 14 (Usp14), a deubiquitinating enzyme (DUB) that associates with the proteasome via its ubiquitin-like (Ubl) domain and is involved in processing ubiquitin chains. Analysis of Usp14 gene products demonstrated that Usp14 undergoes alternative pre-mRNA splicing to produce a full-length form of Usp14 that is capable of binding proteasomes and a form that contains a deletion in the Ubl domain. The full-length form of Usp14 is the only form that appears to be reduced in the axJ mice. Transgenic rescue of the axJ mice with neuronal-specific expression of Usp14 demonstrated that the full-length form of Usp14 was sufficient to restore viability and motor system function to the axJ mice. Biochemical analysis showed that the ubiquitin hydrolyase activity of this form of Usp14 is dependent on the presence of proteasomes, and neuronal expression of full-length Usp14 was able to restore the levels of monomeric ubiquitin in the brains of axJ mice. However, the axJ-rescued mice still displayed the Purkinje cell axonal swellings that are seen in the axJ mice, indicating that this cerebellar alteration is not the primary cause of the axJ movement disorders. These results show that the motor defects observed in the axJ mice are attributable to a neuropathic disease rather than to a muscular disorder and suggest that changes in proteasomal function may contribute to neurological dysfunction in the axJ mice.
authors.affiliation: Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Crimmins
authors.forename: Youngam
authors.initials: Y
authors.lastname: Jin
authors.forename: Crystal
authors.initials: C
authors.lastname: Wheeler
authors.forename: Alexis K
authors.initials: AK
authors.lastname: Huffman
authors.forename: Carlene
authors.initials: C
authors.lastname: Chapman
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Dobrunz
authors.forename: Alan
authors.initials: A
authors.lastname: Levey
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
authors.forename: Julie A
authors.initials: JA
authors.lastname: Wilson
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001259:Ataxia / Q000201:enzymology* / Q000235:genetics*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D025801:Ubiquitin; C469268:Usp14 protein, mouse; D043222:Ubiquitin Thiolesterase