Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA
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...
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2012-09-01
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doaj-30718e37293848ef80c5d6e69c80229b2021-03-22T12:38:38ZengElsevierNeurobiology of Disease1095-953X2012-09-01473416427Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinAGiuseppe Sciamanna0Robert Hollis1Chelsea Ball2Giuseppina Martella3Annalisa Tassone4Andrea Marshall5Dee Parsons6Xinru Li7Fumiaki Yokoi8Lin Zhang9Yuqing Li10Antonio Pisani11David G. Standaert12Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata and Fondazione Santa Lucia, I.R.C.C.S., Roma, ItalyCenter for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USACenter for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USAClinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata and Fondazione Santa Lucia, I.R.C.C.S., Roma, ItalyClinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata and Fondazione Santa Lucia, I.R.C.C.S., Roma, ItalyCenter for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USACenter for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USACenter for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USACenter for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USACenter for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USACenter for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USAClinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata and Fondazione Santa Lucia, I.R.C.C.S., Roma, ItalyCenter for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author at: Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, 1719 6th Ave South, CIRC 516, Birmingham, AL 35242, USA. Fax: +1 205 996 6580.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 effects are specific for cholinergic interneurons, as recordings from nigral dopaminergic neurons revealed normal responses. Amphetamine stimulated dopamine release was also unaltered. These results demonstrate a cell-autonomous effect of Dyt1 deletion on striatal cholinergic function. Therapies directed at modifying the function of cholinergic neurons may prove useful in the treatment of the human disorder.http://www.sciencedirect.com/science/article/pii/S0969996112001611DYT1TorsinADystoniaCholinergic interneuronAcetylcholineConditional knock-out |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Giuseppe Sciamanna Robert Hollis Chelsea Ball Giuseppina Martella Annalisa Tassone Andrea Marshall Dee Parsons Xinru Li Fumiaki Yokoi Lin Zhang Yuqing Li Antonio Pisani David G. Standaert |
spellingShingle |
Giuseppe Sciamanna Robert Hollis Chelsea Ball Giuseppina Martella Annalisa Tassone Andrea Marshall Dee Parsons Xinru Li Fumiaki Yokoi Lin Zhang Yuqing Li Antonio Pisani David G. Standaert Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA Neurobiology of Disease DYT1 TorsinA Dystonia Cholinergic interneuron Acetylcholine Conditional knock-out |
author_facet |
Giuseppe Sciamanna Robert Hollis Chelsea Ball Giuseppina Martella Annalisa Tassone Andrea Marshall Dee Parsons Xinru Li Fumiaki Yokoi Lin Zhang Yuqing Li Antonio Pisani David G. Standaert |
author_sort |
Giuseppe Sciamanna |
title |
Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA |
title_short |
Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA |
title_full |
Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA |
title_fullStr |
Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA |
title_full_unstemmed |
Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA |
title_sort |
cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsina |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2012-09-01 |
description |
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 effects are specific for cholinergic interneurons, as recordings from nigral dopaminergic neurons revealed normal responses. Amphetamine stimulated dopamine release was also unaltered. These results demonstrate a cell-autonomous effect of Dyt1 deletion on striatal cholinergic function. Therapies directed at modifying the function of cholinergic neurons may prove useful in the treatment of the human disorder. |
topic |
DYT1 TorsinA Dystonia Cholinergic interneuron Acetylcholine Conditional knock-out |
url |
http://www.sciencedirect.com/science/article/pii/S0969996112001611 |
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