Tuesday, May 10, 2005

More suprising findings about DNA instability in neurons

This months' Nature Medicine has a news item about a mouse mutant with defects in its ability to repair DNA damage. Neurons in these mutant mice have severe genomic damage, and are targeted for apoptosis (active removal), which results in a greatly reduced cerebellum. But if the scientists also interfered with the apoptosis pathways, the resultant double mutant mice had fairly good cerebellum size and function, despite presumably harboring a whole zoo of neuronal DNA damage!

Nijmegen breakage syndrome (NBS) is a rare human disease characterized by sensitivity to radiation and predisposition to cancer. In addition, humans with NBS have microcephaly (a much reduced brain size) and occasionally are mentally retarded. The gene which is mutated in humans with NBS, called NBS1 (known as Nbn in mice), is needed to repair DNA damage.

Special "Knockout mice" which lack Nbn gene function only in the nervous system accumulate DNA damage in neurons. Their neurological defects in the cerebellum, for the first time, mimics defects seen in humans with NBS. Scientists investigating these mutant mice found evidence for activation of the apoptosis pathway , which is used to remove injured or excess cells.

The big suprise, for me, came when the scientists introduced an additional mutation in the mice to remove function of the important apoptosis protein p53 (made by the gene Trp53). In mice which had mutations in both genes, the neurological problems were strongly reduced relative to mice lacking only Nbn function! Even Nbn mutant mice who additionally had only lost one functional copy of Trp53 still did better than the mice with both Trp53 copies normal.

The authors are at pains to emphasize that the double mutant mice are not normal. (In fact, the mice develop tumors and die young, because Trp53 is also important for tumor supression in the rest of the body. Thus the mice do not live long enough to evaluate how well their brains function into old age.) To underscore this point, it would have been nice to demonstrate aneuploidy or chromosomal damage in surviving double mutant neurons. Futhermore, the authors review the strong evidence that neurons in normal mice do undergo apoptosis throughout life. Thus the mice may have developed cerebellar problems later. Still, to have one devastating mutation ameliorate the effects of another seems a bit like stopping a bullet with a bullet.

While I could foresee that disabling the apoptosis pathway would lead to survival of cells that would normally be culled, I am just astonished that neurons with this sort of DNA damage would contribute anything at all to brain function. The double mutant mice are able to walk along a narrow rod (very easy for normal mice, but I wouldn't want to try) and could scurry along with the best of them, while their single mutant siblings had severe ataxia. Amazing.

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