Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice

The gracile axonal dystrophy (gad) mouse is an autosomal recessive mutant that shows sensory ataxia at an early stage, followed by motor ataxia at a later stage(1). Pathologically, the mutant is characterized by 'dying-back' type axonal degeneration and formation of spheroid bodies in nerve terminals(2-5) Recent pathological observations have associated brain ageing and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates(6,7). In gad mice, accumulation of amyloid beta-protein and ubiquitin-positive deposits occur retrogradely along the sensory and motor nervous systems(8,9). We previously reported that the gad mutation was transmitted by a gene on chromosome 5 (refs 10,11). Here we find that the gad mutation is caused by an in-frame deletion including exons 7 and 8 of Uchl1, encoding the ubiquitin carboxy-terminal hydrolase (UCH) isozyme (Uch-ll) selectively expressed in the nervous system and testis(12-15). The gad allele encodes a truncated Uch-ll lacking a segment of 42 amino acids containing a catalytic residue(16). As Uch-ll is thought to stimulate protein degradation by generating free monomeric ubiquitin(16-18), the gad mutation appears to affect protein turnover. Our data suggest that altered function of the ubiquitin system directly causes neurodegeneration, The gad mouse provides a useful model for investigating human neurodegenerative disorders.