Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.

NAD 池的维护对于神经元的存活至关重要。在神经退行性疾病中，维持 NAD 池的能力会下降。我们发现，NMNAT2（关键的神经元 NAD 产生酶）水平较低会导致视网膜对神经退行性损伤的易感性。作为概念证明，过度表达全长人类 NMNAT2 的基因疗法具有神经保护作用。为了在药理学上靶向 NMNAT2，我们发现表没食子儿茶素没食子酸酯 (EGCG) 可以通过 NMNAT2 和 NMN 依赖性机制驱动神经元中 NAD 的产生。我们通过 NAD 挽救途径的药理学和遗传抑制证实了这一点。 EGCG 对啮齿动物（混合性别）和人类视网膜神经变性模型具有神经保护作用。由于 EGCG 的药物性质较差，我们将其用作工具化合物来生成新型小分子，以驱动神经元 NAD 的产生并提供神经保护。随着进一步的药物开发，这类 NMNAT2 靶向小分子可能对神经退行性疾病产生重要的治疗影响。