Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence.
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in the MJD1 gene resulting in an expanded polyglutamine repeat in the ataxin-3 protein. To study the course of the disease, we generated transgenic mice for SCA3 using full-length ataxin-3 constructs containing 15, 70, or 148 CAG repeats, respectively. Control mice (15 CAGs) were phenotypically normal and had no neuropathological findings. However, mice transgenic for ataxin-3 with expanded polyglutamine repeats were severely affected by a strong neurological phenotype with tremor, behavioral deficits, strongly reduced motor and exploratory activity, a hunchback, and premature death at 3 to 6 months of age. Neuropathological examination by immunohistochemical staining revealed ubiquitin- and ataxin-3-positive intranuclear inclusion bodies in a multitude of neurons. Directing ataxin-3 with 148 CAGs to the nucleus revealed an even more pronounced phenotype with more inclusions and earlier death, whereas mice transgenic with the same construct but attached to a nuclear export signal developed a milder phenotype with less inclusions. These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo.
Bichelmeier
Ulrike
U
Department of Medical Genetics, University of Tübingen, D-72076 Tübingen, Germany.
Schmidt
Thorsten
T
Hübener
Jeannette
J
Boy
Jana
J
Rüttiger
Lukas
L
Häbig
Karina
K
Poths
Sven
S
Bonin
Michael
M
Knipper
Marlies
M
Schmidt
Werner J
WJ
Wilbertz
Johannes
J
Wolburg
Hartwig
H
Laccone
Franco
F
Riess
Olaf
O
D000818:Animals; D000067699:Ataxin-3; D001415:Back / Q000002:abnormalities; D002467:Cell Nucleus / Q000378:metabolism*; D005106:Exploratory Behavior; D007150:Immunohistochemistry / Q000379:methods; D002479:Inclusion Bodies / Q000378:metabolism; D017827:Machado-Joseph Disease / Q000150:complications* / Q000378:metabolism / Q000401:mortality / Q000523:psychology; D001523:Mental Disorders / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009410:Nerve Degeneration / Q000209:etiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013194:Staining and Labeling; D014018:Tissue Distribution; D014202:Tremor / Q000209:etiology; D018911:Trinucleotide Repeats; D025801:Ubiquitin / Q000378:metabolism
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D025801:Ubiquitin; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3