In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD+ hydrolase, SARM1. In healthy neurons SARM1 is autoinhibited, but single amino acid changes can abolish autoinhibition leading to constitutively active SARM1 enzymes that promote degeneration when expressed in cultured neurons. To investigate whether naturally occurring human variants might disrupt SARM1 autoinhibition and potentially contribute to risk for neurodegenerative disease, we assayed the enzymatic activity of all 42 rare SARM1 alleles identified among 8507 amyotrophic lateral sclerosis (ALS) patients and 9671 controls. We then intrathecally injected mice with virus expressing SARM1 constructs to test the capacity of an ALS-associated constitutively active SARM1 variant to promote neurodegeneration in vivo. Twelve out of 42 SARM1 missense variants or small in-frame deletions assayed exhibit constitutive NADase activity, including more than half of those that are unique to the ALS patients or that occur in multiple patients. There is a > 5-fold enrichment of constitutively active variants among patients compared to controls. Expression of constitutively active ALS-associated SARM1 alleles in cultured dorsal root ganglion (DRG) neurons is pro-degenerative and cytotoxic. Intrathecal injection of an AAV expressing the common SARM1 reference allele is innocuous to mice, but a construct harboring SARM1V184G, the constitutively active variant found most frequently among the ALS patients, causes axon loss, motor dysfunction, and sustained neuroinflammation. These results implicate rare hypermorphic SARM1 alleles as candidate genetic risk factors for ALS and other neurodegenerative conditions.

中文翻译：

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诱导神经病变的组成型活性 SARM1 变体在 ALS 患者中富集

作为对损伤的反应，神经元激活由 NAD+ 水解酶 SARM1 启动的有组织的轴突自我毁灭程序。在健康的神经元中，SARM1 是自抑制的，但单个氨基酸的变化可以消除自抑制，导致在培养的神经元中表达时促进退化的组成型活性 SARM1 酶。为了研究天然存在的人类变异是否可能破坏 SARM1 自身抑制并可能导致神经退行性疾病的风险，我们分析了在 8507 名肌萎缩侧索硬化症 (ALS) 患者和 9671 名对照中鉴定的所有 42 个罕见 SARM1 等位基因的酶活性。然后，我们向小鼠鞘内注射表达 SARM1 构建体的病毒，以测试与 ALS 相关的组成型活性 SARM1 变体促进体内神经退行性变的能力。分析的 42 个 SARM1 错义变体或小的框内缺失中，有 12 个表现出组成型 NADase 活性，其中超过一半是 ALS 患者独有的或发生在多个患者中的那些。与对照组相比，患者的组成型活性变体富集 > 5 倍。组成型活性 ALS 相关 SARM1 等位基因在培养的背根神经节 (DRG) 神经元中的表达是促退行性和细胞毒性的。鞘内注射表达常见 SARM1 参考等位基因的 AAV 对小鼠无害，但含有 SARM1V184G（在 ALS 患者中最常见的组成型活性变体）的构建体会导致轴突丢失、运动功能障碍和持续的神经炎症。