Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Exp Neurol. 2020 May;327:113219. doi: 10.1016/j.expneurol.2020.113219. Epub 2020 Jan 31.
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 hSOD1 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.
肌萎缩侧索硬化症（ALS）的特征是运动神经元的进行性退化。来自不同 ALS 模型的星形胶质细胞在共培养中诱导运动神经元死亡。增强 NAD 的可用性，或增加 NAD 依赖性去酰基酶 SIRT3 和 SIRT6 的表达，可消除它们在细胞培养模型中的神经毒性。为了确定增加 ALS 小鼠模型中 NAD 可用性的效果，我们使用了两种策略，即消耗 NAD 的酶（CD38）的缺失和生物可利用的 NAD 前体（烟酰胺核糖苷，NR）的补充。CD38 的缺失对两种与 hSOD1 相关的 ALS 小鼠模型的存活没有影响。另一方面，NR 补充延迟了运动神经元退化，减少了脊髓中的神经炎症标志物，似乎改变了肌肉代谢，并适度增加了 hSOD1 小鼠的存活。此外，我们发现 ALS 患者脊髓中参与 NAD 合成的酶（NAMPT 和 NMNAT2）的表达发生改变，SIRT6 的表达降低，这表明该神经保护途径在人类病理学中存在缺陷。我们的数据表明增加 NAD 水平在 ALS 中的治疗潜力。此外，结果表明，用于增强 NAD 水平的方法对 ALS 模型的生物学结果具有决定性影响，这表明使用生物可利用的前体来提高 NAD 水平将是 ALS 的首选治疗策略。
