Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice.
Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice.
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DOI：
10.1016/j.ntt.2014.10.004
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发表时间：
2014-11
影响因子：
2.9
通讯作者：
Simon DK
中科院分区：
文献类型：
--
作者：
Dai Y;Clark J;Zheng K;Kujoth GC;Prolla TA;Simon DK
线粒体DNA(MtDNA)突变被认为在衰老和与年龄相关的神经退行性疾病(如帕金森氏病(PD))中起致病作用。为了支持这一点，携带有校对缺陷形式的线粒体DNA聚合酶γ(PolgD257A)的“Polg Mutator”小鼠体内高水平的线粒体DNA突变会导致过早衰老表型。然而，这一发现与正常衰老过程的相关性受到了质疑，因为即使在年轻的Polg Mutator小鼠中，突变的数量也比小鼠正常衰老期间的水平更多，这些小鼠没有明显的表型。多巴胺能神经元对1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)的易感性随着年龄的增长而增加，我们推测这可能部分是由于体细胞mtDNA突变随着年龄的增长而积累。如果正确，那么年轻的(2~3个月大)Polg突变小鼠的突变水平应该足以增加对MPTP的易感性。相反，我们发现杂合和纯合子Polg突变小鼠在这个年轻年龄对MPTP的易感性与野生型斜发对照组没有什么不同，通过测量纹状体酪氨酸羟基酶阳性(TH+)终末、纹状体多巴胺及其代谢产物的水平，氧化损伤的标志，或TH+和黑质总神经元的体视学计数。这些意想不到的结果不支持这样的假设，即体细胞mtDNA突变导致多巴胺能神经元对MPTP的年龄相关脆弱性。体细胞mtDNA突变仍有可能影响对其他应激源的易感性，或者需要额外的时间才能表现出有害后果。此外，在我们的研究中没有评估这些年龄较大的小鼠中存在的较高水平的突变的影响，尽管先前的一项研究也没有发现老年小鼠对MPTP的易感性增加。有了这些警告，目前的数据并没有提供证据证明体细胞mtDNA突变在确定MPTP易感性方面的作用。
Mitochondrial DNA (mtDNA) mutations are hypothesized to play a pathogenic role in aging and age-related neurodegenerative diseases such as Parkinson’s disease (PD). In support of this, high levels of somatic mtDNA mutations in “POLG mutator” mice carrying a proofreading-deficient form of mtDNA polymerase γ (PolgD257A) lead to a premature aging phenotype. However, the relevance of this finding to the normal aging process has been questioned as the number of mutations is greater even in young POLG mutator mice, which show no overt phenotype, than levels achieved during normal aging in mice. Vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) increases with age, and we hypothesized that this may result in part from the accumulation with age of somatic mtDNA mutations. If correct, then levels of mutations in young (2~3 month old) POLG mutator mice should be sufficient to increase vulnerability to MPTP. In contrast, we find that susceptibility to MPTP in both heterozygous and homozygous POLG mutator mice at this young age is not different from that of wild type littermate controls as measured by levels of tyrosine hydroxylase positive (TH+) striatal terminals, striatal dopamine and its metabolites, a marker of oxidative damage, or stereological counts of TH+ and total substantia nigra neurons. These unexpected results do not support the hypothesis that somatic mtDNA mutations contribute to the age-related vulnerability of dopaminergic neurons to MPTP. It remains possible that somatic mtDNA mutations influence vulnerability to other stressors, or require additional time for the deleterious consequences to manifest. Furthermore, the impact of the higher levels of mutations present at older ages in these mice was not assessed in our study, although a prior study also failed to detect an increase in vulnerability to MPTP in older mice. With these caveats, the current data do not provide evidence for a role of somatic mtDNA mutations in determining the vulnerability to MPTP.
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