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

Abstract

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. Pathologically, the mutant is characterized by 'dying-back' type axonal degeneration and formation of spheroid bodies in nerve terminals. Recent pathological observations have associated brain ageing and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates. In gad mice, accumulation of amyloid beta-protein and ubiquitin-positive deposits occur retrogradely along the sensory and motor nervous systems. 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-l1) selectively expressed in the nervous system and testis. The gad allele encodes a truncated Uch-l1 lacking a segment of 42 amino acids containing a catalytic residue. As Uch-l1 is thought to stimulate protein degradation by generating free monomeric ubiquitin, 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.

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

“…34 Decreases in its expression, resulting in impairment of the ubiquitin proteasome pathway, have been linked to several neurodegenerative disorders, including Parkinson disease, Alzheimer's disease and HD. [35][36][37] Furthermore, a mouse model with a loss-of-function UCHL1 deletion displays an ataxic phenotype, 38,39 validating the changes seen in SCA7 patient cells.…”

“…This is encouraging given that boosting UCHL1 levels has been suggested as a therapeutic strategy for Alzheimer's disease. 39 However, this initial increase was mitigated at higher levels of ataxin-7 knockdown after treatment with the non-allele-specific siRNA. In contrast, the allelespecific siRNA maintained elevated levels of UCHL1, implying that loss of UCHL1 expression at high doses of non-allele-specific silencing may be caused by loss of normal function of the wild-type ATXN7 protein.…”

The roles of the proteasome pathway in signal transduction and neurodegenerative diseases

“…The role of UCHL1 in human PD is still unclear, but loss of function is known to be deleterious, as recessive deletion of part of this gene causes gracile axonal dystrophy in mice. Although this phenotype is not obviously parkinsonian, it is associated with the formation of ubiquitinated intraneuronal aggregates [72] . 4.3 Huntington's disease and UPS Huntington's disease (HD) is one of fourteen known conditions caused by a CAG trinucleotide repeat expansion that is translated into a polyglutamine (polyQ) tract in the disease protein.…”

Protein monoubiquitylation: targets and diverse functions

“…Possible insight into the pathological function of UCH‐L1 has been provided by Gad (gracile axonal degeneration) mice, which do not express UCH‐L1 as a result of a corresponding gene mutation (Saigoh et al . 1999). The axonal degeneration apparent in these mice suggests that UCH‐L1 is essential for functional maintenance of axons.…”