Abstract
UCHL1 (ubiquitin carboxyterminal hydrolase 1) is a deubiquitinating enzyme that is particularly abundant in neurons. From studies of a spontaneous mutation arising in a mouse line it is clear that loss of function of UCHL1 generates profound degenerative changes in the central nervous system, and it is likely that a proteolytic deficit contributes to the pathology. Here these effects were found to be recapitulated in mice in which the Uchl1 gene had been inactivated by homologous recombination. In addition to the previously documented neuropathology associated with loss of UCHL1 function, axonal swellings were detected in the striatum. In agreement with previously reported findings the loss of UCHL1 function was accompanied by perturbations in ubiquitin pools, but glutathione levels were also significantly depleted in the brains of the knockout mice, suggesting that oxidative defense mechanisms may be doubly compromised. To determine if, in addition to its role in the central nervous system, UCHL1 function is also required for homeostasis of the enteric nervous system the gastrointestinal tract was analyzed in UCHL1 knockout mice. The mice displayed functional changes and morphological changes in gut neurons that preceded degenerative changes in the brain. The changes were qualitatively and quantitatively similar to those observed in wild type mice of much greater age, and strongly resemble changes reported for elderly humans. UCHL1 knockout mice should therefore serve as a useful model of gut aging.
Highlights
UCHL1 is a member of the ubiquitin carboxyterminal hydrolases, a subgroup of the deubiquitinating enzymes
Whereas the UCHL1 protein was abundant in wild type brains it was undetectable in sections from mice homozygous for the targeted gene analyzed by immunohistochemistry (Figures 1C,D)
The finding that UCHL1 null mice have a progressive neurodegenerative phenotype culminating in hindlimb paralysis was not unexpected; our intention in eliminating a portion of the catalytic domain of UCHL1 was to ensure that any protein produced from the gene would be inactive, as is the case for the spontaneous deletion of the seventh and eighth UCHL1 exons in GAD mouse line (Saigoh et al, 1999)
Summary
UCHL1 is a member of the ubiquitin carboxyterminal hydrolases, a subgroup of the deubiquitinating enzymes. In the absence of any conformational change this loop would obstruct access of any ubiquitinated substrate larger than a small peptide, which would explain the restriction of UCHL1 to such substrates in vitro (Larsen et al, 1998). Proposed roles for UCHL1 are the processing of the ubiquitin proprotein by cleavage of the short C terminal peptide, and salvage of ubiquitin from remnants of proteasomal degradation proteins. Both activities have been demonstrated in vitro (Larsen et al, 1998). An obvious mechanism for formation of these conjugates would be transthioesterification with glutathione supplanting the E2 conjugating enzymes or E3 ligases of the ubiquitin
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