Mechanisms of motor neuron toxicity in Kennedy Disease

选择性神经元变性是许多成人发作的神经退行性变的显著特征。 紊乱在这些慢性神经系统疾病中，有一种是由神经系统的扩张引起的。 CAG/谷氨酰胺束。肯尼迪病是这类疾病的一员，其特征是下丘脑的退行性变， 由于雄激素受体基因的第一外显子中的CAG重复序列扩增，导致运动神经元死亡。数据从 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质错误折叠， 聚集并与其他蛋白质异常相互作用，导致激素依赖性下运动神经元 变性和骨骼肌萎缩。尽管在揭示疾病基础方面取得了重大进展， 突变雄激素受体介导选择性运动神经元病理学的途径仍然存在， 不充分理解。最近的研究强调了异常细胞相互作用的重要性， 非神经元细胞参与某些多聚谷氨酰胺和运动神经元疾病的发病机制。 本提案的目的是确定扩大谷氨酰胺雄激素的途径 受体导致选择性神经元损失。我们的中心假设是突变的雄激素受体蛋白 对它们共同支配的下运动神经元和骨骼肌细胞产生毒性作用 导致选择性神经病理学。这一假设是基于我们最近开发的 Kennedy病的基因敲入小鼠模型。我们发现，这个模型再现了神经肌肉和 这种疾病的系统表现。此外，肌肉病理学，这是伴随着证据 和未折叠蛋白反应的激活，先于运动神经元的丧失， 提示非细胞自主毒性的作用。生物化学，细胞和遗传学方法将是 用于更好地理解导致骨骼肌病理学的机制（目的1）， 非细胞自主毒性的作用（目的2），以及未折叠蛋白质反应对细胞毒性的贡献。 疾病表型的发展（目的3）。拟议研究与公共卫生的相关性是 他们将提供新的理解， 神经变性这项工作也有望揭示导致选择性低血糖的机制。 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.