Impact of genetic reduction of NMNAT2 on chemotherapy-induced losses in cell viability in vitro and peripheral neuropathy in vivo

Nicotinamide mononucleotide adenylyl transferases (NMNATs) are essential neuronal maintenance factors postulated to preserve neuronal function and protect against axonal degeneration in various neurodegenerative disease states. We used in vitro and in vivo approaches to assess the impact of NMNAT2 reduction on cellular and physiological functions induced by treatment with a vinca alkaloid (vincristine) and a taxane-based (paclitaxel) chemotherapeutic agent. NMNAT2 null (NMNAT2-/-) mutant mice die at birth and cannot be used to probe functions of NMNAT2 in adult animals. Nonetheless, primary cortical cultures derived from NMNAT2-/- embryos showed reduced cell viability in response to either vincristine or paclitaxel treatment whereas those derived from NMNAT2 heterozygous (NMNAT2+/-) mice were preferentially sensitive to vincristine-induced degeneration. Adult NMNAT2+/- mice, which survive to adulthood, exhibited a 50% reduction of NMNAT2 protein levels in dorsal root ganglia relative to...烟酰胺单核苷酸腺苷酰转移酶（Nicotinamide mononucleotide adenylyl transferases，NMNATs）是一类关键的神经元维持因子，被认为可维持神经元功能，并在多种神经退行性疾病状态下抵御轴突变性。本研究采用体外（in vitro）与体内（in vivo）实验手段，评估NMNAT2表达下调对长春花生物碱类（vinca alkaloid）药物长春新碱（vincristine）及紫杉烷类（taxane-based）药物紫杉醇（paclitaxel）这两种化疗药物处理所诱导的细胞与生理功能的影响。NMNAT2纯合敲除（NMNAT2-/-）突变小鼠会在出生时死亡，无法用于探究成年动物体内NMNAT2的生理功能。尽管如此，来源于NMNAT2-/-胚胎的原代皮层神经元培养物在经长春新碱或紫杉醇处理后，细胞活力显著下降；而来源于NMNAT2杂合子（NMNAT2+/-）小鼠的原代皮层培养物，则对长春新碱诱导的神经元退行性变表现出优先敏感性。能够存活至成年的NMNAT2杂合子小鼠，其背根神经节（dorsal root ganglia）中的NMNAT2蛋白水平相较于……降低50%