Therapeutic strategies to rescue metabolic deficiencies in spinal and bulbar muscular atrophy

挽救脊髓和延髓肌萎缩症代谢缺陷的治疗策略

• 批准号: 10826086
• 负责人: DIANE E MERRY
• 金额: $ 42.9万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10826086
• 关键词: Adult; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Androgen Receptor; Androgens; Bypass; Cell model; Defect; Disease; Disease model; Energy Metabolism; Enzymes; Evaluation; Family; Genetic; Homeostasis; Human; Huntington Disease; Inherited; Ligands; Link; Metabolic; Modeling; Mus; Muscle; Neurodegenerative Disorders; Neuromuscular Diseases; Neuronal Dysfunction; Nicotinamide Mononucleotide; Nuclear; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pattern; Receptor Aggregation; Regimen; Skeletal Muscle; Spinal Cord; Spinocerebellar Ataxias; Therapeutic; Toxic effect; androgenic; insight; metabolomics; mouse model; neuron loss; nicotinamide-beta-riboside; polyglutamine; protein misfolding; public health relevance; spinal and bulbar muscular atrophy; therapeutic evaluation; transcriptome sequencing

Project Summary: Several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and the polyglutamine expansion diseases, result from protein misfolding and accumulation due to genetic and/or environmental causes. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, inherited (X-linked) neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related to other neurodegenerative diseases caused by polyglutamine expansion, including Huntington’s disease and several spinocerebellar ataxias. Although the precise pathways leading to neuronal dysfunction and death are unknown, the evaluation of mouse and cell models of these diseases has yielded mechanistic insights into disease pathogenesis. SBMA stands apart from other polyglutamine diseases in that its onset and progression are dependent on AR androgenic ligands. Metabolomic analyses of muscle and spinal cord from two mouse models of SBMA revealed severe reductions in muscle NAD+ while spinal cord showed no such changes. Treatment with nicotinamide riboside (NR) to restore NAD+ levels was unsuccessful. However, RNA-seq studies revealed substantially reduced levels of muscle NMRK2, which encodes an enzyme required to convert NR to NAD+ in muscle, suggesting a likely reason for both the reduction in NAD+ and its intransigence to NR treatment. We propose to bypass NRK2 through the systemic administration of nicotinamide mononucleotide (NMN) to two mouse models of SBMA with distinct expression patterns of polyglutamine-expanded androgen receptor but common defects in muscle NAD+ levels. The two mouse models of SBMA used within this proposal reproduce the androgen- and polyglutamine- dependent nuclear AR aggregation seen in patients, as well as its consequent toxicity, making studies using these models relevant to human SBMA patients. The successful completion of this study will reveal whether this simple therapeutic regimen could be beneficial for patients with SBMA.

项目摘要： 几种神经退行性疾病，包括阿尔茨海默氏病，帕金森氏病和 多谷氨酰胺扩张疾病是由蛋白质折叠和积累引起的遗传性疾病 和/或环境原因。脊柱和鳞茎肌肉萎缩（SBMA）是一个成人发言权，遗传 （X连锁）神经肌肉疾病是由雄激素内多谷氨酰胺膨胀引起的 受体（AR）;它与由多谷氨酰胺扩张引起的其他神经退行性疾病有关， 包括亨廷顿氏病和几种脊椎动物共济失调。虽然是精确的途径 导致神经元功能障碍和死亡尚不清楚，对小鼠和细胞模型的评估 这些疾病已经对疾病发病机理产生了机械见解。 SBMA除了 其他聚谷氨酰胺疾病的发作和进展取决于AR雄激素 配体。来自SBMA的两个小鼠模型的肌肉和脊髓的代谢组分析显示 肌肉NAD+的严重降低，而脊髓没有显示这种变化。与 烟酰胺核苷（NR）以恢复NAD+水平不成功。但是，RNA-Seq研究 发现肌肉NMRK2的水平大大降低，该酶编码转换所需的酶 NR到NAD+在肌肉中，这可能是降低NAD+的可能原因 进行NR治疗。我们建议通过烟酰胺的系统给药绕过NRK2 单核苷酸（NMN）到两个SBMA的小鼠模型，具有不同的表达模式 多谷氨酰胺扩展的雄激素受体，但肌肉NAD+水平的常见缺陷。两个 该提案中使用的SBMA的小鼠模型又重现了雄激素和聚谷氨酰胺 - 患者观察到的依赖性核AR聚集及其随之而来的毒性，进行研究 使用与人类SBMA患者相关的这些模型。这项研究的成功完成将 揭示这种简单的治疗方案是否对SBMA患者有益。