PDF(Pubmed)
Abstract：
Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.
摘要：
Leber先天性黑蒙9型是由NAD+合成酶NMNAT1突变引起的常染色体隐性视网膜病。尽管NMNAT1的普遍表达，但患者除视网膜变性外没有其他病变。在这里，我们证明了成年小鼠中广泛的NMNAT1耗竭反映了人类病理学，光感受器的选择性损失突出了这些细胞对NMNAT1损失的精致脆弱性。有条件的缺失表明在光感受器内需要NMNAT1。机械上,NMNAT1的缺失激活了NADaseSARM1，轴突变性的中枢执行者，引发光感受器死亡和视力丧失。因此，NMNAT1在光感受器中的基本功能是抑制SARM1,突出了轴突变性和光感受器神经变性之间意想不到的共同机制.这些结果定义了一种新的SARM1依赖性光感受器细胞死亡途径，并将SARM1鉴定为视网膜病变的治疗候选物。
