Dopamine D1 Receptor in mouse models of primary dystonia

描述（由申请人提供）：原发性扭转肌张力障碍（PTD）是一组以扭转肌挛缩为特征的运动障碍，肌张力障碍是唯一的临床症状（震颤除外），没有神经元变性或获得性原因。有多种遗传原因，具有重叠的表型。我们现在已经确定了GNAL的一系列突变，编码G？在没有TOR1A或THAP1突变的早发性扭转肌张力障碍（EOTD）患者中。G ?olf是一种将纹状体多巴胺D1 （D1R）和腺苷A2a （A2AR）受体偶联到腺苷酸环化酶v的G蛋白，因此在纹状体输出的中等大小的棘神经元和胆碱能中间神经元中表达。大量证据支持肌张力障碍中基底神经节功能障碍，尽管其他区域，如小脑和皮质也参与其中。在基底节区，重点是多巴胺D2受体（D2R）和纹状体胆碱能中间神经元。除了酪氨酸羟化酶生物合成途径的突变外，GNAL是第一个直接指出DA信号转导系统是病理生理起源的EOTD基因

DESCRIPTION (provided by applicant): Primary torsion dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, with dystonia as the only clinical sign (except for tremor) and in the absence of neuronal degeneration or an acquired cause. There are multiple genetic causes, with overlapping phenotypes. We have now identified a series of mutations in GNAL, encoding G?olf, in patients with early onset torsion dystonia (EOTD) who do not harbor mutations in TOR1A or THAP1. G?olf is a G protein that couples striatal dopamine D1 (D1R) and adenosine A2a (A2AR) receptors to adenylyl cyclase V. Therefore, it is expressed in striatal output medium size spiny neurons and cholinergic interneurons. Abundant evidence supports dysfunction of the basal ganglia in dystonia, although other regions, e.g. cerebellum and cortex, are also involved. Within the basal ganglia, the focus has been on the dopamine D2 receptor (D2R) and striatal cholinergic interneurons. Other than mutations in the tyrosine hydroxylase biosynthetic pathway, GNAL is the first EOTD gene that directly points to the DA signal transduction system as the origin of pathophysiology, particularly to D1R. TorsinA is a AAA-ATPase protein and Thap1 is a transcription factor. Their specific functions, however, remain enigmatic, particularly as to how their mutations result in dystonia. Therefore, the connection between G?olf and the nigrostriatal dopamine system allows for directed, comparative assays of this system in mouse "models" of the three forms of EOTD. The rationale behind these studies is that dissecting the direct effects and compensatory maladaptations in neurotransmission, particularly dopaminergic and adenosinergic, Gnal heterozygote-null mice will offer clues to pathophysiology in DYT1 (TOR1A) and DYT6 (THAP1) EOTD as well. In Specific Aim 1, it will be determined whether mutations in EOTD genes TOR1A, THAP1 and GNAL result in similar altered DA neurotransmission in the striatum as evidenced by DA level and release, G protein activity, and cAMP production. In Specific Aim 2, baseline and pharmacologically induced behavior will be analyzed in the same genotypes. The molecular counterparts of the behaviors will be assayed via measures of induction of phosphorylation of ERK and DARPP-32, following D1R, D2R, and A2AR receptor agonists and antagonists. In Specific Aim 3, RNA-seq will be performed in the Gnal+/- mouse and THAP1-C54Y knockin mouse, and compared to those in the Tor1a GAG+/-mouse (via collaboration) to identify downstream targets, particularly in neurotransmitter pathways. Identification of a final common pathway in different forms of EOTD will aid in directing discovery of therapeutic targets for this currently incurable disorder.