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Reduced complement of dopaminergic neurons in the substantia nigra pars compacta of mice with a constitutive "low footprint" genetic knockout of alpha-synuclein.
Molecular Brain ( IF 3.3 ) Pub Date : 2020-05-11 , DOI: 10.1186/s13041-020-00613-5
Valeria V Goloborshcheva 1, 2 , Kirill D Chaprov 1, 2 , Ekaterina V Teterina 2 , Ruslan Ovchinnikov 2, 3 , Vladimir L Buchman 1, 2
Affiliation  

Previous studies of the alpha-synuclein null mutant mice on the C57Bl6 genetic background have revealed reduced number of dopaminergic neurons in their substantia nigra pars compacta (SNpc). However, the presence in genomes of the studied mouse lines of additional genetic modifications that affect expression of genes located in a close proximity to the alpha-synuclein-encoding Snca gene makes these data open to various interpretations. To unambiguously demonstrate that the absence of alpha-synuclein is the primary cause of the observed deficit of dopaminergic neurons, we employed a recently produced constituent alpha-synuclein knockout mouse line B6(Cg)-Sncatm1.2Vlb/J. The only modification introduced to the genome of these mice is a substitution of the first coding exon and adjusted short intronic fragments of the Snca gene by a single loxP site. We compared the number of dopaminergic neurons in the SNpc of this line, previously studied B6(Cg)-Sncatm1Rosl/J line and wild type littermate mice. A similar decrease was observed in both knockout lines when compared with wild type mice. In a recently published study we revealed no loss of dopaminergic neurons following conditional inactivation of the Snca gene in neurons of adult mice. Taken together, these results strongly suggest that alpha-synuclein is required for efficient survival or maturation of dopaminergic neurons in the developing SNpc but is dispensable for survival of mature SNpc dopaminergic neurons.

中文翻译:

具有组成型“低足迹”基因敲除α-突触核蛋白的小鼠黑质致密部小鼠多巴胺能神经元补体减少。

以前对C57B16遗传背景的α-突触核蛋白无效突变小鼠的研究表明,黑质致密部(SNpc)中多巴胺能神经元的数量减少了。但是,研究的小鼠品系的基因组中存在其他遗传修饰,这些修饰会影响紧邻编码α-突触核蛋白的Snca基因的基因表达,从而使这些数据可用于各种解释。为了明确证明缺乏α-突触核蛋白是观察到的多巴胺能神经元缺陷的主要原因,我们采用了最近生产的α-突触核蛋白基因敲除小鼠系B6(Cg)-Sncatm1.2Vlb / J。引入这些小鼠基因组的唯一修饰是单个loxP位点取代了Snca基因的第一个编码外显子和经调节的短内含子片段。我们比较了该品系的SNpc,先前研究的B6(Cg)-Sncatm1Rosl / J品系和野生型同窝小鼠的多巴胺能神经元的数量。与野生型小鼠相比,在两个基因敲除品系中都观察到了类似的下降。在最近发表的一项研究中,我们发现成年小鼠神经元中Snca基因的条件失活后,多巴胺能神经元没有丢失。综上所述,这些结果强烈表明,α-突触核蛋白是发育中的SNpc中多巴胺能神经元的有效存活或成熟所必需的,但对于成熟的SNpc多巴胺能神经元的存活是必不可少的。与野生型小鼠相比,在两个基因敲除品系中均观察到类似的下降。在最近发表的一项研究中,我们发现成年小鼠神经元中Snca基因的条件失活后,多巴胺能神经元没有丢失。综上所述,这些结果强烈表明,α-突触核蛋白是发育中的SNpc中多巴胺能神经元的有效存活或成熟所必需的,但对于成熟的SNpc多巴胺能神经元的存活是必不可少的。与野生型小鼠相比,在两个基因敲除品系中都观察到了类似的下降。在最近发表的一项研究中,我们发现成年小鼠神经元中的Snca基因有条件失活后,多巴胺能神经元没有丢失。综上所述,这些结果强烈表明,α-突触核蛋白是发育中的SNpc中多巴胺能神经元的有效存活或成熟所必需的,但对于成熟的SNpc多巴胺能神经元的存活是必不可少的。
更新日期:2020-05-11
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