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Evaluation of the NAD+ biosynthetic pathway in ALS patients and effect of modulating NAD+ levels in hSOD1-linked ALS mouse models.
Experimental Neurology ( IF 4.6 ) Pub Date : 2020-01-31 , DOI: 10.1016/j.expneurol.2020.113219
Benjamin A Harlan 1 , Kelby M Killoy 1 , Mariana Pehar 1 , Liping Liu 1 , Johan Auwerx 2 , Marcelo R Vargas 1
Affiliation  

Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons. Astrocytes from diverse ALS models induce motor neuron death in co-culture. Enhancing NAD+ availability, or increasing the expression of the NAD+-dependent deacylases SIRT3 and SIRT6, abrogates their neurotoxicity in cell culture models. To determine the effect of increasing NAD+ availability in ALS mouse models we used two strategies, ablation of a NAD+-consuming enzyme (CD38) and supplementation with a bioavailable NAD+ precursor (nicotinamide riboside, NR). Deletion of CD38 had no effect in the survival of two hSOD1-linked ALS mouse models. On the other hand, NR-supplementation delayed motor neuron degeneration, decreased markers of neuroinflammation in the spinal cord, appeared to modify muscle metabolism and modestly increased the survival of hSOD1G93A mice. In addition, we found altered expression of enzymes involved in NAD+ synthesis (NAMPT and NMNAT2) and decreased SIRT6 expression in the spinal cord of ALS patients, suggesting deficits of this neuroprotective pathway in the human pathology. Our data denotes the therapeutic potential of increasing NAD+ levels in ALS. Moreover, the results indicate that the approach used to enhance NAD+ levels critically defines the biological outcome in ALS models, suggesting that boosting NAD+ levels with the use of bioavailable precursors would be the preferred therapeutic strategy for ALS.

中文翻译:

评估ALS患者的NAD +生物合成途径以及在hSOD1连接的ALS小鼠模型中调节NAD +水平的作用。

肌萎缩性侧索硬化症(ALS)的特征是运动神经元进行性变性。来自多种ALS模型的星形胶质细胞在共培养物中诱导运动神经元死亡。增强NAD +的可用性,或增加NAD +依赖性脱酰基酶SIRT3和SIRT6的表达,可以消除它们在细胞培养模型中的神经毒性。为了确定在ALS小鼠模型中增加NAD +可用性的影响,我们使用了两种策略,消融消耗NAD +的酶(CD38)和补充可生物利用的NAD +前体(烟酰胺核糖,NR)。CD38的删除对两个hSOD1连接的ALS小鼠模型的存活率没有影响。另一方面,补充NR可延缓运动神经元变性,减少脊髓神经炎症标记,似乎可以改变肌肉代谢并适度增加hSOD1G93A小鼠的存活率。此外,我们发现ALS患者脊髓中NAD +合成相关酶的表达改变(NAMPT和NMNAT2)和SIRT6表达降低,表明这种神经保护途径在人体病理中缺乏。我们的数据表明增加ALS中NAD +水平的治疗潜力。此外,结果表明,用于提高NAD +水平的方法严格定义了ALS模型的生物学结果,表明通过使用可生物利用的前体物来提高NAD +水平将是ALS的首选治疗策略。提示在人类病理中该神经保护途径的缺陷。我们的数据表明增加ALS中NAD +水平的治疗潜力。此外,结果表明,用于提高NAD +水平的方法严格定义了ALS模型的生物学结果,表明通过使用可生物利用的前体物来提高NAD +水平将是ALS的首选治疗策略。提示在人类病理中该神经保护途径的缺陷。我们的数据表明增加ALS中NAD +水平的治疗潜力。此外,结果表明,用于提高NAD +水平的方法严格定义了ALS模型的生物学结果,表明通过使用可生物利用的前体物来提高NAD +水平将是ALS的首选治疗策略。
更新日期:2020-01-31
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