Transgenic Rescue ofataxiaMice with Neuronal-Specific Expression of Ubiquitin-Specific Protease 14

Themutation () is a recessive neurological mutation that results in reduced growth, ataxia, and hindlimb muscle wasting in mice. Thegene encodes ubiquitin-specific protease 14 (), a deubiquitinating enzyme (DUB) that associates with the proteasome via its ubiquitin-like (Ubl) domain and is involved in processing ubiquitin chains. Analysis ofgene products demonstrated thatundergoes 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 themice. Transgenic rescue of themice with neuronal-specific expression of Usp14 demonstrated that the full-length form of Usp14 was sufficient to restore viability and motor system function to themice. 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 ofmice. However, the-rescued mice still displayed the Purkinje cell axonal swellings that are seen in themice, indicating that this cerebellar alteration is not the primary cause of themovement disorders. These results show that the motor defects observed in themice 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 themice.

Duke Scholars

Author Carlene D Moore Neurology, Headache and Pain