1. A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats
- Author
-
Carsten Holzmann, Jana Boy, Thorsten Schmidt, Samy Unser, Tim Karl, Saleh M. Ibrahim, Ulrike Schumann, Ute Grasshoff, Olaf Riess, Ina Schmitt, Franco Laccone, and Hartwig Wolburg
- Subjects
Genetically modified mouse ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Huntingtin ,Offspring ,Intranuclear Inclusion Bodies ,Gene Expression ,Mice, Transgenic ,Late onset ,Disease ,Biology ,lcsh:RC321-571 ,Mice ,SCA3 ,Trinucleotide Repeats ,Spinocerebellar ataxia type 3 ,Chromosomal Instability ,Internal medicine ,medicine ,Animals ,Genetic Predisposition to Disease ,Age of Onset ,Ataxin-3 ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Genetics ,Sex Characteristics ,Movement Disorders ,Brain ,Nuclear Proteins ,Machado-Joseph Disease ,medicine.disease ,Rats ,Motor coordination ,Disease Models, Animal ,Endocrinology ,Neurology ,Mutation ,Disease Progression ,Spinocerebellar ataxia ,MJD ,Polyglutamine ,Machado–Joseph disease ,Transcription Factors - Abstract
Spinocerebellar ataxia type 3 (SCA3), or Machado–Joseph disease (MJD), is caused by the expansion of a polyglutamine repeat in the ataxin-3 protein. We generated a mouse model of SCA3 expressing ataxin-3 with 148 CAG repeats under the control of the huntingtin promoter, resulting in ubiquitous expression throughout the whole brain. The model resembles many features of the disease in humans, including a late onset of symptoms and CAG repeat instability in transmission to offspring. We observed a biphasic progression of the disease, with hyperactivity during the first months and decline of motor coordination after about 1 year of age; however, intranuclear aggregates were not visible at this age. Few and small intranuclear aggregates appeared first at the age of 18 months, further supporting the claim that neuronal dysfunction precedes the formation of intranuclear aggregates.
- Published
- 2010