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The Journal of Neuroscience, November 1, 2006, 26(44):11423-11431; doi:10.1523/JNEUROSCI.3600-06.2006

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Neurobiology of Disease
Transgenic Rescue of ataxia Mice with Neuronal-Specific Expression of Ubiquitin-Specific Protease 14

Stephen Crimmins,¹ Youngam Jin,¹ Crystal Wheeler,¹ Alexis K. Huffman,¹ Carlene Chapman,¹ Lynn E. Dobrunz,¹ Alan Levey,³ Kevin A. Roth,² Julie A. Wilson,¹ and Scott M. Wilson¹

¹Department of Neurobiology, Civitan International Research Center, and ²Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, and ³Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30329

Correspondence should be addressed to Dr. Scott M. Wilson, Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, 1825 University Boulevard, Shelby 914, Birmingham, AL 35294. Email: wilson{at}nrc.uab.edu

The ataxia mutation (ax^J) is a recessive neurological mutation that results in reduced growth, ataxia, and hindlimb muscle wasting in mice. The ax^J 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 ax^J mice. Transgenic rescue of the ax^J 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 ax^J 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 ax^J mice. However, the ax^J-rescued mice still displayed the Purkinje cell axonal swellings that are seen in the ax^J mice, indicating that this cerebellar alteration is not the primary cause of the ax^J movement disorders. These results show that the motor defects observed in the ax^J 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 ax^J mice.

Key words: ataxia; proteasome; ubiquitin; synapse; mutation; transgenic

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Received June 16, 2006; accepted Sept. 17, 2006.

Correspondence should be addressed to Dr. Scott M. Wilson, Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, 1825 University Boulevard, Shelby 914, Birmingham, AL 35294. Email: wilson{at}nrc.uab.edu

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