title: Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (DeltaE) TorsinA in transgenic mice.
abstract: Early onset torsion dystonia is an autosomal dominant movement disorder of variable penetrance caused by a glutamic acid, i.e. DeltaE, deletion in DYT1, encoding the protein TorsinA. Genetic and structural data implicate basal ganglia dysfunction in dystonia. TorsinA, however, is diffusely expressed, and therefore the primary source of dysfunction may be obscured in pan-neuronal transgenic mouse models. We utilized the tyrosine hydroxylase (TH) promoter to direct transgene expression specifically to dopaminergic neurons of the midbrain to identify cell-autonomous abnormalities. Expression of both the human wild type (hTorsinA) and mutant (DeltaE-hTorsinA) protein resulted in alterations of dopamine release as detected by microdialysis and fast cycle voltammetry. Motor abnormalities detected in these mice mimicked those noted in transgenic mice with pan-neuronal transgene expression. The locomotor response to cocaine in both TH-hTorsinA and TH-DeltaE-hTorsinA, in the face of abnormal extracellular DA levels relative to non-transgenic mice, suggests compensatory, post-synaptic alterations in striatal DA transmission. This is the first cell-subtype-specific DYT1 transgenic mouse that can serve to differentiate between primary and secondary changes in dystonia, thereby helping to target disease therapies.
authors.affiliation: Thomas Jefferson University, Department of Neurosurgery, Farber Institute for Neurosciences, Philadelphia, PA 19107, USA.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Page
authors.forename: Li
authors.initials: L
authors.lastname: Bao
authors.forename: Pierrette
authors.initials: P
authors.lastname: Andre
authors.forename: Joshua
authors.initials: J
authors.lastname: Pelta-Heller
authors.forename: Emily
authors.initials: E
authors.lastname: Sluzas
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonzalez-Alegre
authors.forename: Alexey
authors.initials: A
authors.lastname: Bogush
authors.forename: Loren E
authors.initials: LE
authors.lastname: Khan
authors.forename: Lorraine
authors.initials: L
authors.lastname: Iacovitti
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Rice
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Ehrlich
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D020821:Dystonic Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000502:physiology; D009048:Motor Skills / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones; D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine
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