Abstract
DYT1 early-onset generalized dystonia is a hyperkinetic movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Recently, significant progress has been made in studying pathophysiology of DYT1 dystonia using targeted mouse models. Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 knock-down (KD) mice exhibit motor deficits and alterations of striatal dopamine metabolisms, while Dyt1 knockout (KO) and Dyt1 ΔGAG homozygous KI mice show abnormal nuclear envelopes and neonatal lethality. However, it has not been clear whether motor deficits and striatal abnormality are caused by Dyt1 mutation in the striatum itself or the end results of abnormal signals from other brain regions. To identify the brain region that contributes to these phenotypes, we made a striatum-specific Dyt1 conditional knockout (Dyt1 sKO) mouse. Dyt1 sKO mice exhibited motor deficits and reduced striatal dopamine receptor 2 (D2R) binding activity, whereas they did not exhibit significant alteration of striatal monoamine contents. Furthermore, we also found normal nuclear envelope structure in striatal medium spiny neurons (MSNs) of an adult Dyt1 sKO mouse and cerebral cortical neurons in cerebral cortex-specific Dyt1 conditional knockout (Dyt1 cKO) mice. The results suggest that the loss of striatal torsinA alone is sufficient to produce motor deficits, and that this effect may be mediated, at least in part, through changes in D2R function in the basal ganglia circuit.
Highlights
Dystonia is a movement disorder that is exhibited by involuntary, repetitive, sustained muscle contractions or abnormal postures [1]
DYT1 is expressed in multiple brain regions, motor symptoms are prominent in DYT1 dystonia patients
D2R binding activity and alteration of striatal monoamine metabolism were reported in DYT1 dystonia patients [17,18,19]
Summary
Dystonia is a movement disorder that is exhibited by involuntary, repetitive, sustained muscle contractions or abnormal postures [1]. Dystonia is classified into two groups, primary and secondary dystonia. DYT1 early-onset generalized torsion dystonia is an inherited movement disorder and is caused by mutations in DYT1 (TOR1A) coding for torsinA with about 30% penetrance [3]. Most DYT1 dystonia patients have a 3 basepairs deletion (DGAG) in DYT1 in one allele, corresponding to a loss of a glutamic acid residue in the C-terminal region of torsinA [3], while an 18 bp deletion mutation [9] and an Arg288Gln missense mutation [10] have been reported. A frame shift mutation caused by 4 bp-deletion coding for the C-terminal region of torsinA was reported in a possible myoclonusdystonia patient [11]. Ampicillininjected Dyt DGAG heterozygous KI male mice express normal level of striatal torsinA and exhibit normal motor performance, suggesting recovery of torsinA level in the striatum may rescue the motor deficits in Dyt DGAG heterozygous KI male mice [13]
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