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: 

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