Non-Invasive Markers of Neurodegeneration in Movement Disorders

摘要 肌张力障碍是一种神经运动障碍，以持续或间歇性肌肉收缩为特征， 这会导致不正常的动作和姿势。DYT1肌张力障碍是一种常染色体显性遗传性原发性肌张力障碍。 受影响的人是残疾人，许多时候被限制在轮椅上。DYT1肌张力障碍主要由 DYT1/TOR1A外显子5的框内Gag缺失，导致C-末端区域谷氨酸丢失 扭力A(TorsinAΔE)。尽管传统上认为原发性肌张力障碍是一种起源于基底节的疾病，但实际上 越来越清楚的是，同时涉及基底节和小脑的大脑回路是 导致肌张力障碍的症状。与此同时，我们对TorsinA是如何发挥作用的了解很少 特定的细胞类型和跨越特定的大脑区域将释放运动缺陷和病理生理特征 肌张力障碍。为了解决这个问题，我们将利用我们实验团队的三项关键创新 为我们的团队定位以实现这一目标。首先，我们开发了一种分子遗传学方法，可以 选择性地针对特定细胞类型的功能，这样一些细胞仍然缺乏Torsin A，而另一些细胞 功能正常。我们将使用这种方法来专门针对细胞类型，包括：1)中等刺神经元， 基底节内胆碱能神经元、多巴胺受体2神经元和多巴胺能神经元，2) 皮质内的谷氨酸能神经元和小脑内的浦肯野神经元。第二，我们将利用我们的 行为表型和肌电图示肌张力障碍相关缺陷的经验 老鼠模型。我们将使用肌电图术、后肢抱抱和其他方法来量化肌肉的协同收缩。 与肌张力障碍相关的运动缺陷的测试。第三，一项关键的创新将是使用先进的高场脑成像 在11.1特斯拉使用活体多壳层扩散成像评估结构退变，静息状态功能 磁共振成像(FMRI)用于评估功能连通性，感觉诱发fMRI用于评估 整个大脑感觉神经元的完整性。在目标1中，我们将探索细胞特异性对Tor1a(DYT1)ΔGag的影响 杂合子敲入(KI)小鼠。在目标2中，我们将在一个小鼠模型中探索细胞特异性效应 通过Cre重组酶的表达和TorsinA的条件敲除(CKO)。行为表型的使用 而非侵入性神经成像标记物将提供对细胞特异性机制的基本了解 与肌张力障碍相关，为未来的小鼠临床前治疗研究提供翻译读出，以及 这里使用的神经成像标记物将直接翻译成人类。

SUMMARY Dystonia is a neurological movement disorder characterized by sustained or intermittent muscle contractions, which result in abnormal movements and postures. DYT1 dystonia is an autosomal dominant primary dystonia. Affected individuals are disabled and many times confined to a wheelchair. DYT1 dystonia results primarily from an in-frame GAG deletion in exon 5 of DYT1/TOR1A, resulting in a loss of glutamic acid at the C-terminal region of torsinA (torsinAΔE). Although primary dystonia is classically considered a disorder of basal ganglia origin, it is becoming clear that brain circuits that involve both the basal ganglia and cerebellum are fundamental in contributing to the symptoms of dystonia. At the same time, we know very little about how torsinA function in specific cell types and across specific brain regions will unleash motor deficits and pathophysiological signatures of dystonia. To address this question, we will leverage three key innovations from our experimental team that position our group to accomplish this goal. First, we have developed a molecular genetics approach that can selectively target the function of specific cell types, such that some cells remain deficient in torsinA while others function normally. We will use this approach to specifically target cell types including: 1) medium spiny neurons, cholinergic neurons, dopamine receptor 2 neurons, and dopaminergic neurons within basal ganglia, 2) glutaminergic neurons within cortex, and 3) Purkinje neurons within cerebellum. Second, we will leverage our experience in behavioral phenotyping and electromyography to characterize dystonia-related deficits in the mouse models. We will quantify muscle co-contraction using electromyography, hindlimb clasping, and other tests of dystonia-related motor deficits. Third, a key innovation will be to use advanced, high-field brain imaging at 11.1 Tesla using in vivo multi-shell diffusion imaging to assess structural degeneration, resting state functional magnetic resonance imaging (fMRI) to assess functional connectivity, and sensory-evoked fMRI to assess the integrity of sensory neurons across the brain. In Aim 1, we will explore cell-specific effects on Tor1a (Dyt1) ΔGAG heterozygous knock-in (KI) mice. In Aim 2 we will explore cell-specific effects in a mouse model characterized by Cre-recombinase expression and conditional knock-out (cKO) of torsinA. The use of behavioral phenotypes and non-invasive neuroimaging markers will provide fundamental understanding of the cell-specific mechanisms related to dystonia, provide translational read-outs for future preclinical therapeutic studies in mouse, and the neuroimaging markers used here will have direct translation to humans.