Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism.
Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism.
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SIRT1的转基因补充无法减轻骨纹状体多巴胺神经元的急性丧失和MPTP诱导的帕金森氏症的小鼠模型中的急性丧失。
DOI：
10.12688/f1000research.6386.1
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Hori O
中科院分区：
文献类型：
--
作者：
Kitao Y;Ageta-Ishihara N;Takahashi R;Kinoshita M;Hori O
背景1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）的多巴胺（DA）神经元选择性摄取和毒性导致人类帕金森综合征。通过在动物中全身注射MPTP来再现经由线粒体损伤和氧化应激的DA神经元的损失，所述动物用作帕金森综合征和帕金森病（PD）的模型。这项研究旨在测试是否泛神经补充长寿相关的，多效性脱乙酰酶SIRT 1，它赋予部分耐受至少三种模型的中风和神经变性，也可以减轻MPTP诱导的急性病理变化，黑质纹状体DA神经元和邻近的胶质细胞。 结果我们采用了一种朊病毒启动子驱动的Sirt 1转基因小鼠（Sirt 1 Tg），在大脑和脊髓中长期过表达小鼠SIRT 1。对SirtlTg和野生型（WT）雄性同窝出生仔（3 - 4月龄）进行MPTP的腹膜内注射。中脑和纹状体（尾壳核）的急性组织病理学变化进行了评估，连续冠状切片三重标记酪氨酸羟化酶（TH），胶质细胞酸性蛋白（GFAP），和核DNA。在中脑黑质致密部（SNpc）中，Sirt 1 Tg和WT同窝仔之间TH阳性神经元的数量和反应性胶质增生相当。在纹状体中，TH阳性神经末梢的相对荧光强度和胶质增生的水平没有因基因型而异。 结论Sirt 1 Tg和WT同窝小鼠对全身注射MPTP表现出相似的急性组织病理学反应，TH阳性神经元丢失和反应性胶质增生。因此，SIRT 1的遗传补充剂不赋予黑质纹状体DA神经元对MPTP急性毒性的组织学可识别的保护。
Background Dopamine (DA) neuron-selective uptake and toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans. Loss of DA neurons via mitochondrial damage and oxidative stress is reproduced by systemic injection of MPTP in animals, which serves as models of parkinsonism and Parkinson’s disease (PD). This study aimed to test whether pan-neural supplementation of the longevity-related, pleiotropic deacetylase SIRT1, which confers partial tolerance to at least three models of stroke and neurodegeneration, could also alleviate MPTP-induced acute pathological changes in nigrostriatal DA neurons and neighboring glia. Results We employed a line of prion promoter-driven Sirt1-transgenic (Sirt1Tg) mice that chronically overexpress murine SIRT1 in the brain and spinal cord. Sirt1Tg and wild-type (WT) male littermates (3‒4 months old) were subjected to intraperitoneal injection of MPTP. Acute histopathological changes in the midbrain and striatum (caudoputamen) were assessed with serial coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA. In the substantia nigra pars compacta (SNpc) of the midbrain, the number of TH-positive neurons and the reactive gliosis were comparable between the Sirt1Tg and WT littermates. In the striatum, the relative fluorescence intensity of TH-positive nerve terminals and the level of gliosis did not differ by the genotypes. Conclusions Sirt1Tg and WT littermate mice exhibited comparable acute histopathological reactions to the systemic injection of MPTP, loss of TH-positive neurons and reactive gliosis. Thus, the genetic supplementation of SIRT1 does not confer histologically recognizable protection on nigrostriatal DA neurons against acute toxicity of MPTP.