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，包括阿尔茨海默病、帕金森病和帕金森病， 多聚谷氨酰胺扩增疾病，由于遗传性的蛋白质错误折叠和积累而导致。 和/或环境原因。脊髓延髓肌萎缩症（SBMA）是一种成人发病，遗传性， 雄激素内多聚谷氨酰胺扩增引起的（X连锁）神经肌肉疾病 受体（AR）;它与多聚谷氨酰胺扩增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髓小脑共济失调。虽然这些精确的路径 导致神经元功能障碍和死亡是未知的，小鼠和细胞模型的评价， 这些疾病已经产生了对疾病发病机理的机械见解。SBMA除了 其他多聚谷氨酰胺疾病，因为其发病和进展依赖于AR雄激素 配体。两种SBMA小鼠模型的肌肉和脊髓代谢组学分析显示， 肌肉NAD+含量严重降低，而脊髓无此变化。治疗 烟酰胺核苷（NR）恢复NAD+水平是不成功的。然而，RNA-seq研究 揭示了肌肉NMRK 2的水平大幅降低，该蛋白编码转化所需的酶， NR到肌肉中的NAD+，这表明NAD+减少及其顽固性的可能原因 到NR治疗。我们建议通过全身给予烟酰胺来绕过NRK 2 单核苷酸肽（NMN）对两种SBMA小鼠模型具有不同的表达模式， 多聚谷氨酰胺扩增雄激素受体，但肌肉NAD+水平的常见缺陷。两 在该提议中使用的SBMA小鼠模型再现了雄激素和聚谷氨酰胺， 依赖性核AR聚集的患者，以及其随之而来的毒性，使研究 使用这些与人类SBMA患者相关的模型。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。