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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1999-09

AUTHORS

Kazumasa Saigoh, Yu-Lai Wang, Jun-Gyo Suh, Toshiyuki Yamanishi, Yoshihisa Sakai, Hidenori Kiyosawa, Takayuki Harada, Nobutsune Ichihara, Shigeharu Wakana, Tateki Kikuchi, Keiji Wada

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 stage1. Pathologically, the mutant is characterized by 'dying-back' type axonal degeneration and formation of spheroid bodies in nerve terminals2,3,4,5. Recent pathological observations have associated brain ageing and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates6,7. In gad mice, accumulation of amyloid β-protein and ubiquitin-positive deposits occur retrogradely along the sensory and motor nervous systems8,9. 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-l1) selectively expressed in the nervous system and testis12,13,14,15. The gad allele encodes a truncated Uch-l1 lacking a segment of 42 amino acids containing a catalytic residue16. As Uch-l1 is thought to stimulate protein degradation by generating free monomeric ubiquitin16,17,18, 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. More... »

PAGES

47-51

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/12647

DOI

http://dx.doi.org/10.1038/12647

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1007015367

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/10471497


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34 schema:description 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 stage1. Pathologically, the mutant is characterized by 'dying-back' type axonal degeneration and formation of spheroid bodies in nerve terminals2,3,4,5. Recent pathological observations have associated brain ageing and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates6,7. In gad mice, accumulation of amyloid β-protein and ubiquitin-positive deposits occur retrogradely along the sensory and motor nervous systems8,9. 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-l1) selectively expressed in the nervous system and testis12,13,14,15. The gad allele encodes a truncated Uch-l1 lacking a segment of 42 amino acids containing a catalytic residue16. As Uch-l1 is thought to stimulate protein degradation by generating free monomeric ubiquitin16,17,18, 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.
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42 UCH-L1
43 UCHL1
44 accumulation
45 acid
46 aging
47 alleles
48 amino acids
49 amyloid β
50 ataxia
51 autosomal recessive mutant
52 axonal degeneration
53 axonal dystrophy (gad) mouse
54 body
55 brain aging
56 carboxy-terminal hydrolase
57 carboxy-terminal hydrolase (UCH) isozyme
58 catalytic residue16
59 chromosome 5
60 data
61 degeneration
62 degradation
63 deletion
64 deposits
65 disease
66 disorders
67 dystrophy (gad) mouse
68 early stages
69 exon 7
70 formation
71 frame deletion
72 function
73 gad allele
74 gad mice
75 gad mutations
76 genes
77 gracile axonal dystrophy (gad) mouse
78 human neurodegenerative disorders
79 hydrolase
80 hydrolase (UCH) isozyme
81 intragenic deletions
82 isozymes
83 later stage1
84 mice
85 model
86 motor
87 motor ataxia
88 mutants
89 mutations
90 nerve
91 nervous system
92 neurodegeneration
93 neurodegenerative diseases
94 neurodegenerative disorders
95 observations
96 pathological observations
97 progressive accumulation
98 protein
99 protein degradation
100 protein turnover
101 recessive mutant
102 residue16
103 segments
104 sensory
105 sensory ataxia
106 spheroid bodies
107 stage
108 stage1
109 system
110 turnover
111 type axonal degeneration
112 ubiquitin carboxy-terminal hydrolase
113 ubiquitin carboxy-terminal hydrolase (UCH) isozyme
114 ubiquitin system
115 ubiquitin-positive deposits
116 ubiquitinated proteins
117 useful model
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