Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (ΔE) TorsinA in transgenic mice

Autor: Michelle E. Page, Li Bao, Pierrette Andre, Joshua Pelta-Heller, Emily Sluzas, Pedro Gonzalez-Alegre, Alexey Bogush, Loren E. Khan, Lorraine Iacovitti, Margaret E. Rice, Michelle E. Ehrlich
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Zdroj: Neurobiology of Disease, Vol 39, Iss 3, Pp 318-326 (2010)
Druh dokumentu: article
ISSN: 1095-953X
73567779
DOI: 10.1016/j.nbd.2010.04.016
Popis: Early onset torsion dystonia is an autosomal dominant movement disorder of variable penetrance caused by a glutamic acid, i.e. ΔE, 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 (ΔE-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-ΔE-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.
Databáze: Directory of Open Access Journals
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