Mechanisms of motor neuron toxicity in Kennedy Disease

选择性神经元变性是许多成人起病的神经退行性变的显著特征 精神错乱。在这些慢性神经系统疾病中，有一种是由脑血管扩张引起的 CAG/谷氨酰胺纤维束。肯尼迪病是这一组中的一员，其特征是下肢退行性变。 运动神经元是由于雄激素受体基因第一外显子中的CAG重复序列扩大所致。数据来自 包括我们自己的实验室在内的几个实验室证明，突变的雄激素受体蛋白错误折叠， 聚集并异常地与其他蛋白质相互作用，导致激素依赖型下运动神经元 变性和骨骼肌萎缩。尽管在揭开疾病基础方面取得了重大进展， 突变型雄激素受体介导选择性运动神经元病理的途径仍然存在 没有被充分理解。最近的研究强调了异常细胞相互作用的重要性，以及 非神经细胞参与某些多谷氨酰胺和运动神经元病的发病机制。 这项建议的目的是确定扩张的谷氨酰胺雄激素的途径 受体导致选择性神经元丢失。我们的中心假设是突变的雄激素受体蛋白 对低等运动神经元和它们共同支配的骨骼肌细胞都有毒性作用 导致选择性神经元病理。这一假设是基于对我们最近开发的 敲入肯尼迪病小鼠模型。我们发现这个模型再现了神经肌肉和 这种紊乱的全身性表现。此外，肌肉病理学，它伴随着证据 通过激活未折叠的蛋白反应，先于运动神经元的丧失， 暗示了非细胞自主毒性的作用。生化、细胞和遗传方法将是 用来更好地了解导致骨骼肌病理的机制(目标1)， 非细胞自主毒性的作用(目标2)，以及未折叠蛋白对 疾病表型的发展(目标3)。拟议的研究与公共卫生的相关性是 他们将提供新的理解，让我们了解谷氨酰胺束扩张的蛋白质是如何引起 神经退行性变。这项工作还有望揭示导致选择性较低的机制 运动神经元功能障碍和死亡。

Selective neuronal degeneration is a distinguishing feature of many adult onset neurodegenerative disorders. Among these chronic diseases of the nervous system are ones caused by expansions of CAG/glutamine tracts. Kennedy disease, a member of this group, is characterized by degeneration of lower motor neurons due to an expanded CAG repeat in the first exon of the androgen receptor gene. Data from several laboratories including our own demonstrate that the mutant androgen receptor protein misfolds, aggregates and abnormally interacts with other proteins, leading to homone dependent lower motor neuron degeneration and skeletal muscle atrophy. Despite significant advances in unraveling the disease basis, pathways by which the mutant androgen receptor mediates selective motor neuron pathology remain inadequately understood. Recent work has highlighted the importance of abnormal cell interactions and the involvement of non-neuronal cells in the pathogenesis of certain polyglutamine and motor neuron diseases. The objective of this proposal is to identifiy the pathways by which the expanded glutamine androgen receptor causes selective neuronal loss. Our central hypothesis is that the mutant androgen receptor protein exerts toxic effects on both lower motor neurons and the skeletal muscle cells they innervate that together lead to selective neuronal pathology. This hypothesis is based on characterization of our recently developed knock-in mouse model of Kennedy disease. We find that this model reproduces the neuromuscular and systemic manifestations of this disorder. Furthermore, muscle pathology, which is accompanied by evidence of a primary myopathy and by activation of the unfolded protein response, precedes motor neuron loss, suggesting a role for non-cell autonomous toxicity. Biochemical, cellular and genetic approaches will be employed to gain a better understanding of the mechanisms leading to skeletal muscle pathology (Aim 1), the role of non-cell autonomous toxicity (Aim 2), and the contribution of the unfolded protein response to the development of the disease phenotype (Aim 3). The relevance of the proposed studies to public health is that they will provide new understanding of how proteins with expanded glutamine tracts cause neurodegeneration. This work is also expected to reveal insights into mechanisms leading to selective lower motor neuron dysfunction and death.