Mechanisms of motor neuron toxicity in Kennedy Disease

肯尼迪病运动神经元毒性机制

• 批准号: 8027315
• 负责人: ANDREW P LIEBERMAN
• 金额: $ 5.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-05 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8027315
• 关键词: Abnormal Cell; Address; Adult; Affect; Alleles; Androgen Receptor; Animals; Biochemical; CAG repeat; Cell Communication; Cells; Cessation of life; Chronic Disease; Code; Core Facility; Data; Degenerative Disorder; Development; Disease; Environment; Exons; Functional disorder; Gene Mutation; Gene Targeting; Genes; Genetic; Glutamine; Goals; Hormonal; Hormones; Impairment; Kennedy Syndrome; Knock-in Mouse; Knowledge; Laboratories; Lead; Length; Link; Mediating; Modeling; Modification; Molecular; Motor Neuron Disease; Motor Neurons; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle satellite cell; Muscular Atrophy; Myoblasts; Myopathy; Nerve; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neurons; Outcome; Partner in relationship; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Proteins; Public Health; Receptor Gene; Research; Research Personnel; Role; Severity of illness; Site; Skeletal Muscle; Testing; Toxic effect; Transgenes; Ubiquitin; Work; base; cell type; disease phenotype; effective therapy; human disease; insight; male; member; motor neuron degeneration; mouse model; multicatalytic endopeptidase complex; muscle regeneration; mutant; neuromuscular; neuron loss; neurotoxicity; new therapeutic target; novel therapeutic intervention; polyglutamine; programs; protein degradation; receptor; receptor function; recombinase; regenerative; response; spinal and bulbar muscular atrophy; ubiquitin ligase

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.

选择性神经元变性是许多成人发病的神经退行性疾病的显著特征