Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis
Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis
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DOI：
10.1073/pnas.0607423103
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发表时间：
2006-10-24
影响因子：
11.1
通讯作者：
Appel, Stanley H.
中科院分区：
文献类型：
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作者：
Beers, David R.;Henkel, Jenny S.;Appel, Stanley H.
肌萎缩性侧索硬化症（ALS）是一种影响成人运动神经元的神经退行性疾病，最常见的遗传形式是由普遍表达的Cu2+/Zn2+超氧化物歧化酶（SOD1）的显性突变引起的。最近的研究表明，神经胶质细胞可能参与家族性ALS动物模型的运动神经元损伤。为了确定突变体SOD1（mSOD1(G93A)）在中枢神经系统小胶质细胞中的表达是否与运动神经元损伤有关，我们将不能发育髓样细胞和淋巴样细胞的PU.1（-/-）小鼠接受骨髓移植，产生供体源性小胶质细胞。来自过表达mSOD1（G93A）的小鼠的供体来源小胶质细胞（一种家族性ALS动物模型）移植到PU.1（-/-）小鼠体内后，不会引起无力、运动神经元损伤或ALS样疾病。为了确定mSOD1（G93A）在运动神经元和星形胶质细胞以及小胶质细胞中的表达是否需要产生运动神经元疾病，我们将PU.1（-/-）小鼠与mSOD1（G93A）小鼠杂交。在mSOD1 (G93A) /聚氨酯。与接受mSOD1（G93A）表达细胞的小鼠或mSOD1（G93A）小鼠相比，1（-/-）小鼠的野生型供体来源小胶质细胞减缓了运动神经元的丢失，延长了疾病持续时间和生存期。体外研究证实，野生型小胶质细胞的神经毒性低于类似培养的mSOD1（G93A）小胶质细胞。与野生型小胶质细胞相比，mSOD1（G93A）小胶质细胞产生和释放更多的超氧化物和亚硝酸盐，并诱导更多的神经元死亡。这些数据表明，mSOD1（G93A）的表达导致激活和神经毒性的小胶质细胞，并提示mSOD1（G93A）在小胶质细胞中的表达缺乏可能有助于运动神经元的保护。本研究证实了小胶质细胞作为一把双刃剑的重要性，并重点阐述了在神经退行性疾病中靶向小胶质细胞对最小化细胞毒性和最大化神经保护的重要性。
The most common inherited form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motoneurons, is caused by dominant mutations in the ubiquitously expressed Cu2+/Zn2+ superoxide dismutase (SOD1). Recent studies suggest that glia may contribute to motoneuron injury in animal models of familial ALS. To determine whether the expression of mutant SOD1 (mSOD1(G93A)) in CNS microglia contributes to motoneuron injury, PU.1(-/-) mice that are unable to develop myeloid and lymphoid cells received bone marrow transplants resulting in donor-derived microglia. Donor-derived microglia from mice overexpressing mSOD1(G93A), an animal model of familial ALS, transplanted into PU.1(-/-) mice could not induce weakness, motoneuron injury, or an ALS-like disease. To determine whether expression of mSOD1(G93A) in motoneurons and astroglia, as well as microglia, was required to produce motoneuron disease, PU.1(-/-) mice were bred with mSOD1(G93A) mice. In mSOD1(G93A)/PU.1(-/-) mice, wild-type donor-derived microglia slowed motoneuron loss and prolonged disease duration and survival when compared with mice receiving mSOD1(G93A) expressing cells or mSOD1(G93A) mice. In vitro studies confirmed that wild-type microglia were less neurotoxic than similarly cultured mSOD1(G93A) microglia. Compared with wild-type microglia, mSOD1(G93A) microglia produced and released more superoxide and nitrite + nitrate, and induced more neuronal death. These data demonstrate that the expression of mSOD1(G93A) results in activated and neurotoxic microglia, and suggests that the lack of mSOD1(G93A) expression in microglia may contribute to motoneuron protection. This study confirms the importance of microglia as a double-edged sword, and focuses on the importance of targeting microglia to minimize cytotoxicity and maximize neuroprotection in neurodegenerative diseases.