Chromosome-specific accumulation of aneuploidy in the aging mouse brain
Chromosome-specific accumulation of aneuploidy in the aging mouse brain
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DOI：
10.1093/hmg/dds375
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发表时间：
2012-12-15
影响因子：
3.5
通讯作者：
Montagna, Cristina
中科院分区：
文献类型：
--
作者：
Faggioli, Francesca;Wang, Tao;Montagna, Cristina
染色体非整倍体，即整个染色体的获得或丢失，是病理状况的标志，也是出生缺陷和癌症的一个因果因素。许多研究表明，非整倍体细胞在小鼠和人类的大脑中存在频率很高，这表明马赛克非整倍体与正常的大脑功能是相容的，并引发了关于其后果的问题。为了探索非整倍体在衰老过程中对功能衰退和认知功能丧失的可能贡献，我们使用了定量、双标记期间荧光原位杂交方法来比较4月龄和28月龄小鼠大脑皮层中1、7、14、15、16、18、19和Y染色体的非整倍体水平。我们发现，非整倍体以染色体特异性的方式随着年龄的增长而积累，染色体7、18和Y受到的影响最严重，即在28个月大的动物中，染色体18的非神经元性脑核高达9.8。虽然在早期，神经元和神经胶质细胞都受到同样的影响，但年龄相关的增加仅限于非神经元核。在同一动物的小脑或脾脏中未观察到年龄相关的非整倍体增加。从平均超过8条染色体外推到所有20条小鼠染色体的非整倍体的平均频率将表明老年小鼠大脑的非整倍体频率接近50。如此高水平的基因组不稳定性很可能是与年龄相关的神经变性的一个因素。
Chromosomal aneuploidy, the gain or loss of whole chromosomes, is a hallmark of pathological conditions and a causal factor of birth defects and cancer. A number of studies indicate that aneuploid cells are present at a high frequency in the brain of mice and humans, suggesting that mosaic aneuploidies are compatible with normal brain function and prompting the question about their consequences. To explore the possible contribution of aneuploidy to functional decline and loss of cognitive functions during aging, we used a quantitative, dual-labeling interphase-fluorescence in situ hybridization approach to compare aneuploidy levels of chromosomes 1, 7, 14, 15, 16, 18, 19 and Y in the cerebral cortex of 4- and 28-month-old mice. We show that aneuploidy accumulates with age in a chromosome-specific manner, with chromosomes 7, 18 and Y most severely affected, i.e. up to 9.8 of non-neuronal brain nuclei in 28-month-old animals for chromosome 18. While at early age, both neuronal and glial cells are affected equally, the age-related increase was limited to the non-neuronal nuclei. No age-related increase in aneuploidy was observed in the cerebellum or in the spleen of the same animals. Extrapolating the average frequencies of aneuploidy from the average over 8 chromosomes to all 20 mouse chromosomes would indicate an almost 50 aneuploidy frequency in aged mouse brain. Such high levels of genome instability could well be a factor in age-related neurodegeneration.