TY - JOUR
T1 - Chromosome-specific accumulation of aneuploidy in the aging mouse brain
AU - Faggioli, Francesca
AU - Wang, Tao
AU - Vijg, Jan
AU - Montagna, Cristina
N1 - Funding Information:
The work of the authors was supported by grants from the NIH (AG17242 and AG032117 to J.V.).
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/dds375
DO - 10.1093/hmg/dds375
M3 - Article
C2 - 22962300
AN - SCOPUS:84870312272
SN - 0964-6906
VL - 21
SP - 5246
EP - 5253
JO - Human molecular genetics
JF - Human molecular genetics
IS - 24
M1 - dds375
ER -