Generation and Analysis of Gene-Targeted Mouse Models for Oppenheim's Early-Onset Dyt1 Dystonia

A trinucleotide deletion of GAG in the DYT1 gene that encodes torsinA protein is implicated in the neurological movement disorder of Oppenheim's early-onset dystonia. The function of torsinA and the role of the mutation in causing dystonia are unknown. To gain insight into these unknowns, we made two gene-targeted mouse models: a knockin Dyt1 DeltaGAG (KI) to mimic the mutation found in DYT1 dystonic patients and a knockdown with reduced expression of Dyt1 (KD). KI mice exhibited deficient performance on the beam-walking test, a measure of fine motor coordination and balance, and increased locomotive activity. Ubiquitin- and torsinA-containing aggregates were found in neurons of the pontine nuclei of these mice. KI mice also showed dopaminergic system alterations including a significant decrease in striatal dopamine metabolite 4-hydroxy, 3-methoxyphenacetic acid and a reduction of dopamine receptor types 1 (D1) and 2 (D2). The reduction in the level of D2 receptors may be the cause of the elimination of corticostriatal long-term depression (LTD) also detected in KI mice. Further motor learning behavioral testing revealed a severe deficiency of motor skill adaptation in KI mice that may be correlated with the absence of LTD. KD mice that expressed close to 60% of normal torsinA level showed that a reduced level of torsinA even in the absence of mutant protein is adequate to alter the motor behavioral development of mice. These mice, like the KI mice, had deficient performance on the beam-walking test and had increased locomotive activity. They also had a significantly reduced level of 4-dihydroxyphenylacetic acid, another dopamine metabolite. Our results show that the DeltaGAG mutation in Dyt1 causes abnormalities in fine motor coordination and balance, spontaneous locomotive activity level, and a decline in motor skill adaptation. A reduction in D1 and D2 receptor levels that appears to affect D2-receptor dependent corticostriatal LTD ablation may be the mechanism responsible for the motor skill transfer deficit. In addition, the similarity in behavioral phenotype between the two mutant mouse lines indicates that the DeltaGAG mutation is most likely either a loss-of-function or dominant negative mutation, and not a gain-of-function mutation.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular and Integrative Physiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Dang, Mai Tu

Contributors dc:contributor

• Yuqing Li

• Biology, Neuroscience

Language dc:language

eng

Identifier

(MiAaPQ)AAI3250230

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/87242