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首页> 外文期刊>Molecular and Cellular Biology >Differential Impairment of Catecholaminergic Cell Maturation and Survival by Genetic Mitochondrial Complex II Dysfunction
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Differential Impairment of Catecholaminergic Cell Maturation and Survival by Genetic Mitochondrial Complex II Dysfunction

机译：遗传性线粒体复合体II功能异常对儿茶酚胺能细胞成熟和存活的差异性损害

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The SDHD gene (subunit D of succinate dehydrogenase) has been shown to be involved in the generation of paragangliomas and pheochromocytomas. Loss of heterozygosity of the normal allele is necessary for tumor transformation of the affected cells. As complete SdhD deletion is lethal, we have generated mouse models carrying a “floxed” SdhD allele and either an inducible (SDHD-ESR strain) or a catecholaminergic tissue-specific (TH-SDHD strain) CRE recombinase. Ablation of both SdhD alleles in adult SDHD-ESR mice did not result in generation of paragangliomas or pheochromocytomas. In contrast, carotid bodies from these animals showed smaller volume than controls. In accord with these observations, the TH-SDHD mice had decreased cell numbers in the adrenal medulla, carotid body, and superior cervical ganglion. They also manifested inhibited postnatal maturation of mesencephalic dopaminergic neurons and progressive cell loss during the first year of life. These alterations were particularly intense in the substantia nigra, the most affected neuronal population in Parkinson's disease. Unexpectedly, TH+ neurons in the locus coeruleus and group A13, also lacking the SdhD gene, were unaltered. These data indicate that complete loss of SdhD is not sufficient to induce tumorigenesis in mice. They suggest that substantia nigra neurons are more susceptible to mitochondrial damage than other catecholaminergic cells, particularly during a critical postnatal maturation period.
机译：已经证明 SDHD 基因（琥珀酸脱氢酶的D亚基）与副神经节瘤和嗜铬细胞瘤的发生有关。正常等位基因杂合性的丧失对于受影响细胞的肿瘤转化是必需的。由于完整的 SdhD 删除具有致命性，因此我们生成了带有“固定的” SdhD 等位基因和诱导型（SDHD-ESR株）或儿茶酚胺能组织特异性（ TH-SDHD株）CRE重组酶。成年SDHD-ESR小鼠的两个 SdhD 等位基因均未消融，未导致副神经节瘤或嗜铬细胞瘤的产生。相反，来自这些动物的颈动脉体显示出比对照组小的体积。根据这些观察结果，TH-SDHD小鼠的肾上腺髓质，颈动脉体和上颈神经节细胞数量减少。他们还显示出生后第一年中脑多巴胺能神经元的产后成熟受到抑制，并且细胞逐渐丧失。在帕金森氏病中受影响最大的神经元黑质黑质中，这些变化尤为严重。出乎意料的是，蓝藻和A13组中也缺少 SdhD 基因的TH + 神经元未改变。这些数据表明 SdhD 的完全丧失不足以诱导小鼠肿瘤发生。他们认为黑质神经元比其他儿茶酚胺能细胞更容易发生线粒体损伤，特别是在出生后的关键时期。

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