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

项目总结： 几种神经退行性疾病，包括阿尔茨海默氏症、帕金森氏症和 多谷氨酰胺扩张性疾病，由遗传导致的蛋白质错误折叠和堆积引起 和/或环境原因。脊髓和延髓肌萎缩症(SBMA)是一种成人起病的遗传性疾病。 (X连锁)由雄激素内多聚谷氨酰胺膨胀引起的神经肌肉疾病 受体(AR)；它与其他由聚谷氨酰胺扩张引起的神经退行性疾病有关， 包括亨廷顿氏病和几种脊髓小脑性共济失调。尽管精确的路径 导致神经元功能障碍和死亡的原因尚不清楚，小鼠和细胞模型的评估 这些疾病已经对疾病的发病机制产生了机械性的见解。SBMA与 其他多谷氨酰胺疾病，其发生和发展依赖于AR雄激素 配基。两种SBMA模型小鼠肌肉和脊髓的代谢分析 肌肉NAD+严重减少，而脊髓无此变化。通过以下方式治疗 烟酰胺核苷(NR)恢复NAD+水平不成功。然而，RNA-SEQ研究 显示肌肉NMRK2的水平显著降低，它编码一种转换所需的酶 肌肉中的NR到NAD+，这可能是NAD+减少和不妥协的原因 到NR处理。我们建议通过全身应用烟酰胺来绕过NRK2 单核苷酸(NMN)对两种SBMA小鼠模型的作用 多聚谷氨酰胺扩大的雄激素受体，但在肌肉NAD+水平上普遍存在缺陷。两个人 这项建议中使用的SBMA小鼠模型复制了雄激素和多谷氨酰胺- 在患者中看到的依赖核AR聚集，以及由此产生的毒性，正在进行研究 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 揭示这一简单的治疗方案是否对SBMA患者有益。

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.