RIP1 kinase is proposed to play a critical role in driving necroptosis and inflammation in neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS). Preclinical studies indicated that while pharmacological inhibition of RIP1 kinase can ameliorate axonal pathology and delay disease onset in the mutant SOD1 transgenic (SOD1-Tg) mice, genetic blockade of necroptosis does not provide benefit in this mouse model. To clarify the role of RIP1 kinase activity in driving pathology in SOD1-Tg mice, we crossed SOD1-Tgs to RIP1 kinase-dead knock-in mice, and measured disease progression using functional and histopathological endpoints. Genetic inactivation of the RIP1 kinase activity in the SOD1-Tgs did not benefit the declining muscle strength or nerve function, motor neuron degeneration or neuroinflammation. In addition, we did not find evidence of phosphorylated RIP1 accumulation in the spinal cords of ALS patients. On the other hand, genetic inactivation of RIP1 kinase activity ameliorated the depletion of the neurotransmitter dopamine in a toxin model of dopaminergic neurodegeneration. These findings indicate that RIP1 kinase activity is dispensable for disease pathogenesis in the SOD1-Tg mice while inhibition of kinase activity may provide benefit in acute injury models.

RIP1 激酶被认为在驱动神经退行性疾病（包括肌萎缩侧索硬化症 (ALS)）中的坏死性凋亡和炎症中发挥关键作用。临床前研究表明，虽然 RIP1 激酶的药理学抑制可以改善 SOD1 转基因 (SOD1-Tg) 突变小鼠的轴突病理并延缓疾病发作，但对坏死性凋亡的遗传阻断并不能在该小鼠模型中提供益处。为了阐明 RIP1 激酶活性在 SOD1-Tg 小鼠病理驱动中的作用，我们将 SOD1-Tgs 与 RIP1 激酶死亡敲入小鼠杂交，并使用功能和组织病理学终点测量疾病进展。SOD1-Tgs 中 RIP1 激酶活性的遗传失活对肌肉力量或神经功能下降、运动神经元退化或神经炎症无益。此外，我们没有发现 ALS 患者脊髓中磷酸化 RIP1 积累的证据。另一方面，RIP1激酶活性的遗传失活改善了多巴胺能神经变性毒素模型中神经递质多巴胺的消耗。这些发现表明 RIP1 激酶活性对于 SOD1-Tg 小鼠的疾病发病机制是可有可无的，而激酶活性的抑制可能在急性损伤模型中提供益处。