Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a CAG repeat tract that affects the MJD1 gene which encodes the ataxin-3 protein. In order to analyze whether symptoms caused by ataxin-3 with an expanded repeat are reversible in vivo, we generated a conditional mouse model of SCA3 using the Tet-Off system. We used a full-length human ataxin-3 cDNA with 77 repeats in order to generate the responder mouse line. After crossbreeding with a PrP promoter mouse line, double transgenic mice developed a progressive neurological phenotype characterized by neuronal dysfunction in the cerebellum, reduced anxiety, hyperactivity, impaired Rotarod performance and lower body weight gain. When ataxin-3 expression was turned off in symptomatic mice in an early disease state, the transgenic mice were indistinguishable from negative controls after 5 months of treatment. These results show that reducing the production of pathogenic ataxin-3 indeed may be a promising approach to treat SCA3, provided that such treatment is applied before irreversible damage has taken place and that it is continued for a sufficiently long time.
Boy
Jana
J
Department of Medical Genetics, University of Tuebingen, Tuebingen, Germany.
Schmidt
Thorsten
T
Wolburg
Hartwig
H
Mack
Andreas
A
Nuber
Silke
S
Böttcher
Martin
M
Schmitt
Ina
I
Holzmann
Carsten
C
Zimmermann
Frank
F
Servadio
Antonio
A
Riess
Olaf
O
D000818:Animals; D000067699:Ataxin-3; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3