Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

Abstract

A single GAG deletion in Exon 5 of the TOR1A gene is associated with a form of early-onset primary dystonia showing less than 40% penetrance. To provide a framework for cellular and systems study of DYT1 dystonia, we characterized the genetic, behavioral, morphological and neurochemical features of transgenic mice expressing either human wild-type torsinA (hWT) or mutant torsinA (hMT1 and hMT2) and their wild-type (WT) littermates. Relative to human brain, hMT1 mice showed robust neural expression of human torsinA transcript (3.90X). In comparison with WT littermates, hMT1 mice had prolonged traversal times on both square and round raised-beam tasks and more slips on the round raised-beam task. Although there were no effects of genotype on rotarod performance and rope climbing, hMT1 mice exhibited increased hind-base widths in comparison to WT and hWT mice. In contrast to several other mouse models of DYT1 dystonia, we were unable to identify either torsinA-and ubiquitin-positive cytoplasmic inclusion bodies or nuclear bleb formation in hMT1 mice. High-performance liquid chromatography with electrochemical detection was used to determine cerebral cortical, striatal, and cerebellar levels of dopamine (DA), norepinephrine, epinephrine, serotonin, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid. Although there were no differences in striatal DA levels between WT and hMT1 mice, DOPAC and HVA concentrations and DA turnover (DOPAC/DA and HVA/DA) were significantly higher in the mutants. Our findings in DYT1 transgenic mice are compatible with previous neuroimaging and postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in hMT1 mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia.

Commentary: Dopaminergic dysfunction in DYT1 dystonia

“…TorsinA-containing aggregates in neurons, perinuclear inclusion bodies or blebbing of the nuclear membrane were seen in some of the previous studies in transgenic animals, specifically in brain stem nuclei (Dang et al, 2005;Goodchild et al, 2005;Shashidharan et al, 2005;Grundmann et al, 2007), but, in agreement with other studies (e.g., Sharma et al, 2005), Zhao et al (2008) found no such abnormalities in the hMT1 mice. The question of whether inclusion body pathology is specific to the transgenic mouse models, or whether it is also part of human DYT1 disease remains somewhat controversial.…”

“…In their studies of hMT1 mice, Zhao et al (2008) observed increases in hind-base width measured by footprint analysis, and traversal times and slip counts on raised beam running tasks, while performance on an accelerating Rotarod paradigm was normal. This pattern of behavioral abnormalities differs in some respects from that documented in the other studies, specifically those reported with a similar panel of tests by Grundmann et al in one of the other DYT1-over-expressing mouse lines (see above, Grundmann et al, 2007).…”

“…The recent paper by Zhao et al in Experimental Neurology (Zhao et al, 2008) characterizes anatomical, behavioral and biochemical features of one of the strains that over-express mutant human torsinA, hMT1 mice, which were generated by Sharma et al (Sharma et al, 2005). Other animals from the series generated by Sharma et al (Sharma et al, 2005), including animals over-expressing human wild-type torsinA (hWT) and a second (different) line of animals over-expressing human mutant torsinA (hMT2), were also initially examined in the study by Zhao et al (2008) but were then not further considered, because expression levels of human torsinA in these animals were found to be low.…”

“…In a recent issue of Experimental Neurology, Zhao et al (2008) have provided a thorough behavioral, anatomic, and biochemical characterization of a mouse line that over-expresses human mutant torsinA, with particular emphasis on the possible role of dopaminergic dysfunction in these animals. This commentary provides an overview of the clinical and genetic features of the human disease and of the available transgenic mouse models for DYT1 dystonia, and discusses the evidence favoring the role of dopamine in the clinical manifestations of the disease.…”

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…For instance, dystonia may result from disturbances in dopaminergic transmission assumed to affect strongly basal ganglia activity [183]. Thus, dystonia may develop either acutely or delayed (tardive dystonia), in normal individuals treated with dopamine-receptor blocking agents, or can be a sign of other diseases with disturbed dopamine metabolism, such as PD, levodopa-responsive dystonia, or DYT1 [184][185][186][187][188][189]. Transient dystonia has also been observed in monkeys treated with the dopaminergic neurotoxin MPTP [190][191][192].…”