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.

项目概要： 多种神经退行性疾病，包括阿尔茨海默病、帕金森病和 多聚谷氨酰胺扩张疾病，由遗传性蛋白质错误折叠和积累引起 和/或环境原因。脊髓和延髓肌萎缩症 (SBMA) 是一种成人发病的遗传性 由雄激素内聚谷氨酰胺扩张引起的（X连锁）神经肌肉疾病 受体（AR）；它与聚谷氨酰胺扩张引起的其他神经退行性疾病有关， 包括亨廷顿舞蹈症和几种脊髓小脑性共济失调。虽然具体路径 导致神经元功能障碍和死亡的原因尚不清楚，对小鼠和细胞模型的评估 这些疾病使人们对疾病发病机制有了深入的了解。 SBMA 与众不同 其他多聚谷氨酰胺疾病，其发病和进展依赖于 AR 雄激素 配体。对两种 SBMA 小鼠模型的肌肉和脊髓的代谢组学分析显示 肌肉 NAD+ 严重减少，而脊髓没有表现出这种变化。治疗用 烟酰胺核苷 (NR) 恢复 NAD+ 水平未成功。然而，RNA-seq研究 揭示了肌肉 NMRK2 的水平大幅降低，该 NMRK2 编码一种转化所需的酶 肌肉中 NAD+ 的 NR 变化，表明 NAD+ 减少及其不妥协的可能原因 至NR治疗。我们建议通过全身施用烟酰胺来绕过NRK2 单核苷酸（NMN）到两种具有不同表达模式的 SBMA 小鼠模型 多聚谷氨酰胺扩展的雄激素受体，但肌肉 NAD+ 水平存在常见缺陷。两人 本提案中使用的 SBMA 小鼠模型再现了雄激素和聚谷氨酰胺 患者体内观察到的依赖性核 AR 聚集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。本研究的顺利完成将 揭示这种简单的治疗方案是否对 SBMA 患者有益。