X-Message-Number: 12436 Date: Sat, 18 Sep 1999 22:34:14 -0400 From: Jan Coetzee <> Subject: brain ageing Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice Kazumasa Saigoh1, 2, 5, Yu-Lai Wang1, 5, Jun-Gyo Suh1, Toshiyuki Yamanishi1, 2, Yoshihisa Sakai1, Hidenori Kiyosawa1, Takayuki Harada1, Nobutsune Ichihara3, Shigeharu Wakana4, Tateki Kikuchi3 & Keiji Wada1 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 terminals2-5. Recent pathological observations have associated brain ageing and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates6, 7. In gad mice, accumulation of amyloid -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 testis12-15. 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 ubiquitin16-18, 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. 1. Departments of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan. 3. Animal Models for Human Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan. 2. Department of Neurology, Kinki University School of Medicine, Osakasayama, Osaka, 589-8511, Japan. 4. Department of Genetics, Central Institute for Experimental Animals, Kawasaki, 216, Japan. 5. These authors contributed equally to this work. Correspondence should be addressed to K Wada. e-mail: Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=12436