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

NEUROBIOLOGY OF DISEASE

卷:39

Article

Page, Michelle E.²  Bao, Li^3,4  Andre, Pierrette⁵  Pelta-Heller, Joshua⁵  Sluzas, Emily⁵  Gonzalez-Alegre, Pedro⁶  Bogush, Alexey⁵  Khan, Loren E.^1,7,8  Iacovitti, Lorraine⁵  Rice, Margaret E.^3,4  Ehrlich, Michelle E.^1,5 

[1] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA

[2] Thomas Jefferson Univ, Dept Neurosurg, Farber Inst Neurosci, Philadelphia, PA 19107 USA

[3] NYU, Sch Med, Dept Neurosurg, New York, NY 10016 USA

[4] NYU, Sch Med, Dept Physiol & Neurosci, New York, NY 10016 USA

[5] Thomas Jefferson Univ, Dept Neurol, Coll Med, Farber Inst Neurosci, Philadelphia, PA 19107 USA

[6] Univ Iowa, Dept Neurol, Carver Coll Med, Iowa City, IA 52242 USA

[7] Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA

[8] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA

关键词: Dystonia;    Tyrosine hydroxylase;    Dopamine;    DYT1;    TorsinA;    Striatum;    Microdialysis;    Voltammetry;   

DOI  :  10.1016/j.nbd.2010.04.016

来源: Elsevier

【 摘 要 】

Early onset torsion dystonia is an autosomal dominant movement disorder of variable penetrance caused by a glutamic acid, i.e. Delta E, 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 (Delta E-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-Delta E-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. (C) 2010 Elsevier Inc. All rights reserved.

【 授权许可】

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