Novel Genetic Mouse Model to Study the Consequences of TorsinA Dysfunction

描述（由申请人提供）：肌张力障碍是最常见的三大运动障碍之一，从相对年轻的发病开始就会导致持续的残疾。到目前为止，其机制在很大程度上是未知的。它不被认为是一种神经退行性疾病，并提示大脑可塑性异常。在一位散发性迟发性局灶性肌张力障碍患者中，我们最近发现了一种新的罕见的TOR1A序列变体（p.F205I）。TOR1A突变是家族性早发性全身性肌张力障碍（DYT1, c.g g）的已知原因。在揭示了p.F205I变异损害TorsinA功能的硅和体外证据后，我们建立了敲入突变小鼠模型来测试其行为意义。在初步研究中，我们发现F205I突变小鼠在运动学习任务中具有稳健且可复制的行为异常。我们建议进一步开发这种新的小鼠模型，并利用它来了解F205I TorsinA引起的脑活动和神经病理学的变化及其与行为的关系。F205I TOR1A小鼠模型为建立TorsinA功能障碍、神经元病理和行为改变之间的因果关系提供了有用的工具。通过进一步了解TorsinA生物学，我们希望加速对肌张力障碍治疗的见解。

DESCRIPTION (provided by applicant): Dystonia is among the top 3 prevalent movement disorders and a cause of unremitting disability from a relatively young onset. As yet, its mechanisms are largely unknown. It is not considered a neurodegenerative disease and abnormalities in brain plasticity are suggested. In a patient with sporadic, late-onset, focal dystonia, we recently identified a novel rare sequence variant of TOR1A (p.F205I). TOR1A mutation is a known cause of familial early-onset, generalized dystonia (DYT1, c.GAG). After revealing in silico and in vitro evidence that the p.F205I variant impairs TorsinA function, we developed a knockin mutation mouse model to test the behavioral significance. In preliminary studies, we have found that F205I mutant mice have robust and replicable behavioral abnormalities in a motor learning task. We propose to further develop this novel mouse model and use it to understand the changes in brain activity and neuropathology due to F205I TorsinA and their relationship to behavior. The F205I TOR1A mouse model provides a useful tool to establish the causal relationship between TorsinA dysfunction, neuronal pathology and altered behavior. By furthering knowledge of TorsinA biology, we hope to accelerate insights for the treatment of dystonia. PUBLIC HEALTH RELEVANCE: Dystonia is an involuntary movement disorder that is a cause of significant disability. The pathogenesis of dystonia remains unclear. Consequently, current treatment modalities have both limited efficacy and significant side effects. We propose to develop a novel animal model based on a rare TOR1A sequence variant identified in an individual with late-onset, focal dystonia. This novel mouse model has the potential to provide critical insights into the relationship between TorsinA dysfunction and behavioral sequelae. These studies will advance our understanding of the contribution of this gene to dystonia and related neurological diseases.