The reentry of post-mitotic neurons into the cell cycle has been touted as a possible contributory factor to neurodegenerative diseases, including Alzheimer’s disease (see recent live discussion and ARF related news story). However, the series of events that may lead to the reexpression of cell cycle components in these cells is uncertain. Now, in today’s Nature, researchers from The Jackson Laboratory, Bar Harbor, Maine, and Tufts University, North Grafton, Massachusetts, report that oxidative stress may play a key role.
First author Jeffrey Klein and colleagues, working under the direction of Susan Ackerman, came to this conclusion after identifying the mutation responsible for the harlequin (Hq) mouse. These mice are hairless in the absence of a wildtype copy of the Hq gene but also exhibit ataxia and lose neurons from the cerebellum as they age. Klein et al. localized the mutation responsible, an insertion of approximately nine kilobases of proviral DNA, to intron 1 of the apoptosis-inducing factor (Aif) gene. This insertion results in about an 80 percent reduction in the expression of Aif in many organs of Hq mice, including the cerebellum and the rest of the brain.
Aif is an oxidoreductase that is normally confined between the inner and outer membranes of the mitochondria but can be triggered to migrate to the nucleus where it can induce apoptosis. The oxidoreductase domain of Aif is homologous to hydrogen peroxide scavenging proteins from bacteria, suggesting that it may protect cells from oxidation. Klein et al. confirmed this by demonstrating that granule cells from the cerebellum of homozygous Hq mice are more susceptible to peroxide-induced apoptosis.
So what has all this to do with the cell cycle? Knowing that a link has been made between oxidative stress and cell cycle abnormalities, the authors looked in harlequin and wild type mice for the smoking gun of cell cycle re-entry, DNA synthesis. They found that in contrast to their normal littermates, the cerebellum of Hq/Hq mice had many cells with new DNA and that these same cells stained positive for the protein GABAA receptor kinase 6, which is specifically expressed by neurons in the inner granule layer. Furthermore, the number of granule cells synthesizing DNA grew as the animals aged, which is in keeping with the usual slow progression of ataxia in the Hq mice.
Interestingly, other neurons are unaffected by the Hq mutation. Purkinje cells, for example, do not show signs of DNA synthesis, suggesting that while oxidative stress and cell cycle may be linked, additional, highly cell-specific factors are also critical.—Tom Fagan
- Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002 Sep 26;419(6905):367-74. PubMed.