Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Antioxid Redox Signal. 2024 Sep;41(7-9):573-589. doi: 10.1089/ars.2023.0360. Epub 2024 Jul 8.
Increasing nicotinamide adenine dinucleotide (NAD) availability has been proposed as a therapeutic approach to prevent neurodegeneration in amyotrophic lateral sclerosis (ALS). Accordingly, NAD precursor supplementation appears to exert neuroprotective effects in ALS patients and mouse models. The mechanisms mediating neuroprotection remain uncertain but could involve changes in multiple cell types. We investigated a potential direct effect of the NAD precursor nicotinamide mononucleotide (NMN) on the health of cultured induced pluripotent stem cell (iPSC)-derived human motor neurons and in motor neurons isolated from two ALS mouse models, that is, mice overexpressing wild-type transactive response DNA binding protein-43 (TDP-43) or the ALS-linked human superoxide dismutase 1 with the G93A mutation (hSOD1). NMN treatment increased the complexity of neuronal processes in motor neurons isolated from both mouse models and in iPSC-derived human motor neurons. In addition, NMN prevented neuronal death induced by trophic factor deprivation. In mouse and human motor neurons expressing ALS-linked mutant superoxide dismutase 1, NMN induced an increase in glutathione levels, but this effect was not observed in nontransgenic or TDP-43 overexpressing motor neurons. In contrast, NMN treatment normalized the TDP-43 cytoplasmic mislocalization induced by its overexpression. NMN can directly act on motor neurons to increase the growth and complexity of neuronal processes and prevent the death induced by trophic factor deprivation. Our results support a direct beneficial effect of NAD precursor supplementation on the maintenance of the neuritic arbor in motor neurons. Importantly, this was observed in motor neurons isolated from two different ALS models, with and without involvement of TDP-43 pathology, supporting its therapeutic potential in sporadic and familial ALS. 41, 573-589.
增加烟酰胺腺嘌呤二核苷酸（NAD）的可用性已被提议作为一种预防肌萎缩侧索硬化症（ALS）神经退行性变的治疗方法。因此，NAD 前体补充似乎对 ALS 患者和小鼠模型发挥神经保护作用。介导神经保护的机制尚不确定，但可能涉及多种细胞类型的变化。我们研究了 NAD 前体烟酰胺单核苷酸（NMN）对培养的诱导多能干细胞（iPSC）衍生的人运动神经元以及从两种 ALS 小鼠模型（即过度表达野生型反式激活反应 DNA 结合蛋白 43（TDP-43）的小鼠或具有 G93A 突变的 ALS 相关人类超氧化物歧化酶 1（hSOD1））分离的运动神经元的健康的潜在直接影响。NMN 处理增加了从小鼠模型和 iPSC 衍生的人运动神经元中分离的运动神经元的神经元过程的复杂性。此外，NMN 可防止营养因子剥夺引起的神经元死亡。在表达 ALS 相关突变型超氧化物歧化酶 1 的小鼠和人运动神经元中，NMN 诱导谷胱甘肽水平升高，但在非转基因或 TDP-43 过表达运动神经元中未观察到这种作用。相比之下，NMN 处理可使 TDP-43 过表达引起的细胞质定位异常正常化。NMN 可直接作用于运动神经元，增加神经元过程的生长和复杂性，并防止营养因子剥夺引起的死亡。我们的研究结果支持 NAD 前体补充对运动神经元中神经突树突的维持具有直接有益作用。重要的是，这在两种不同的 ALS 模型（包括涉及 TDP-43 病理学和不涉及 TDP-43 病理学的模型）中分离的运动神经元中观察到，支持其在散发性和家族性 ALS 中的治疗潜力。41,573-589.
