Thursday, March 03, 2005

Chromosomal changes in normal human brain cells

Yesterday's Journal of Neuroscience has a fascinating brief report describing a suprisingly high frequency of aneuploidy, or abnormal chomosomal number, in normal human brain cells. About 4% of all the human brain cells (this includes neurons and non-neuronal cells) obtained from normal subjects show increases or decreases in the number of copies of chromosome 21. ( Another group, with overall lower estimates, still arrives at about 5% of neurons with some chromosomal change.)

In any living creature, one of the most critical aspects of cell division is chromosomal segregation , which insures that each of the two daughter cells inheirits exactly the same number of chromosomes (for most animals, 2 of each non-sex chromosome) as the original mother cell. This process is very carefully checked, because a daughter with too many or too few chromosomes might express genes to incorrect levels or give rise to further generations of cells with even more changes. Abnormalities in chromosomal segregation, which result in aneuploidy , are associated with diseases including Down's Syndrome and cancers.

The authors of this study had shown several years ago that developing mouse brains have large numbers of aneuploid dividing cells. Most of the chromosomal mixup appears to occur during the last division of the neuroblasts (parent cells to the neurons), when the neurons themselves are being generated. Again in mice, they have been able to show that changes in chromosome number have measurable consequences in terms of changes in gene expression, although how these events affects the overall health of the animals is not certain. The same research grop has even more recently found a mouse mutant with increased numbers of these damaged cells, possibly because the damaged cells fail to be cleared during natural cleanup events which occur in the developing brain. The significance of the new human study is that they can show that these chromosomal changes in a new mammal, and that they survive into adulthood.

Getting back to Down's syndrome, it has been speculated that overexpression of certain genes on chromosome 21 (since there are 3 copies around) stresses and kills neurons, and that neuronal death may in turn cause some of the cognitive deficits in these people. In light of that theory, it seems really suprising, then, that up to 3 percent of "brain cells" in normal people have four copies of chromosome 21. How are these cells even alive??? The only explanations I can think of are that one needs a group effect to get toxicity, or that the "brain cells" getting scored don't include very many neurons.

No comments: