May 15, 2012

Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA

Neurobiology of Disease
Giuseppe SciamannaDavid G Standaert

Abstract

DYT1 dystonia, a common and severe primary dystonia, is caused by a 3-bp deletion in TOR1A which encodes torsinA, a protein found in the endoplasmic reticulum. Several cellular functions are altered by the mutant protein, but at a systems level the link between these and the symptoms of the disease is unclear. The most effective known therapy for DYT1 dystonia is the use of anticholinergic drugs. Previous studies have revealed that in mice, transgenic expression of human mutant torsinA under a non-selective promoter leads to abnormal function of striatal cholinergic neurons. To investigate what pathological role torsinA plays in cholinergic neurons, we created a mouse model in which the Dyt1 gene, the mouse homolog of TOR1A, is selectively deleted in cholinergic neurons (ChKO animals). These animals do not have overt dystonia, but do have subtle motor abnormalities. There is no change in the number or size of striatal cholinergic cells or striatal acetylcholine content, uptake, synthesis, or release in ChKO mice. There are, however, striking functional abnormalities of striatal cholinergic cells, with paradoxical excitation in response to D2 receptor activation and loss of muscarinic M2/M4 receptor inhibitory function. These ef...Continue Reading

  • References39
  • Citations22

References

  • References39
  • Citations22

Citations

Mentioned in this Paper

Quinpirole Hydrochloride
Neuro-Oncological Ventral Antigen 2
Beta-Actin
Choline
Amphetamine
Dominant-Negative Mutation
Phosphate buffers
TOR1A gene
Physiologic Pulse
Arcturus

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