Transgenic Rescue ofataxia Mice with Neuronal-Specific Expression of Ubiquitin-Specific Protease 14

Journal Article

Theataxiamutation (axJ) is a recessive neurological mutation that results in reduced growth, ataxia, and hindlimb muscle wasting in mice. TheaxJgene 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 ofUsp14gene products demonstrated thatUsp14undergoes 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 theaxJmice. Transgenic rescue of theaxJmice with neuronal-specific expression of Usp14 demonstrated that the full-length form of Usp14 was sufficient to restore viability and motor system function to theaxJmice. 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 ofaxJmice. However, theaxJ-rescued mice still displayed the Purkinje cell axonal swellings that are seen in theaxJmice, indicating that this cerebellar alteration is not the primary cause of theaxJmovement disorders. These results show that the motor defects observed in theaxJmice 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 theaxJmice.

Full Text

Duke Authors

Cited Authors

  • Crimmins, S; Jin, Y; Wheeler, C; Huffman, AK; Chapman, C; Dobrunz, LE; Levey, A; Roth, KA; Wilson, JA; Wilson, SM

Published Date

  • November 1, 2006

Published In

Volume / Issue

  • 26 / 44

Start / End Page

  • 11423 - 11431

Published By

Electronic International Standard Serial Number (EISSN)

  • 1529-2401

International Standard Serial Number (ISSN)

  • 0270-6474

Digital Object Identifier (DOI)

  • 10.1523/jneurosci.3600-06.2006


  • en