Oxidative Stress Triggers Neuronal Cell-Cycle Reentry

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

Comments

  1. This is a very thorough study that provides the Hq mutant mouse as the "first in vivo model for studying the role of oxidative stress on aberrant cell cycle re-entry and subsequent apoptosis." Thus, it links two classes of
    phenomena that have been described in the AD brain. In addition, the authors describe a selective effect on death of neurons in the cerebellum and retina. They convincingly demonstrate that other sets of neurons are resistant to the
    cell death they demonstrate in cerebellum and retina. The authors comment that "Similar to many gene products involved in neurodegenerative and other disorders, the expression pattern of AIF (the gene affected in their mutant) is much wider than the tissues phenotypically affected." They suggest that unaffected sets of neurons may be resistant to cell death by virtue of parallel mechanisms for coping with, in this case, peroxide production. This is a concept that has broad applicability beyond the class of challenge referred to here. It is notable that authors do not find differential selectivity to cell death in the mutant mice when other challenges are presented, including serum starvation.

    In this paper both terms "cell cycle" and "apoptosis" are variously used. Certainly the two are related in ways that are not yet completely defined. However, certain specific commonalities are known. For example cyclin B and CDK 1 are required for cell death as well as being important components of the cell cycle. (See Bob Freeman "The cell cycle and neuronal cell death" in Cell Death and Diseases of the Nervous System, V. Koliatsos and R Ratan eds, Humana Press, 1999, for a review of the relation between the cell cycle and apototic cell death.)

    As is true of a nice paper, there are many issues raised. Limiting to those that relate to AD, how important is it that the selectivity found in the Hq mutant mice is restricted to cells that are traditionally unaffected in AD? Is the expression of cell cycle and cell death seen in AD through the same mechanism suggested in the Hq mutant? It is probable that other challenges, such as growth factor changes, that do not demonstrably affect the Hq mutants, play a significant role in AD. Although much attention has been recently devoted to the C terminal fragment of APP in AD, this paper suggests another class of mechanism whose potential applicability to AD requires experimental exploration.

    View all comments by Paul Coleman

  2. I loved this paper.This work makes a compelling case for the involvement of oxidative stress in unscheduled cell cycle re-entry of postmitotic neurons, with consequent apoptosis. What is remarkable is the selective vulnerability of cerebellar and retinal neurons, despite of the fact that the AIF gene, in which the ecotropic provirus inserted, is expressed throughout brain. The Hq mutant mouse might therefore serve as a model not only for studying how oxidative damage leads to activation of the cell cycle in cerebellar neurons, but also for delineating the basis of the resistance to this death scheme of hippocampal and cerebral neurons for example. It is also curious that only neurons of the CNS seem to be affected in the Hq mouse – or was this the only tissue studied here? I did a search for more comprehensive phenotypic description of the Hq mouse, but found only one report about ichthyosis, a condition in which the skin becomes thickened, devoid of hair, and scaly. AIF is, apparently, expressed ubiquitously in normal tissues and in a variety of cancer cell lines. This Hq mouse model would also be useful for determining why mutation of the AIF gene affects only certain tissue types.

    View all comments by Inez Vincent

  3. Harlequin and Alzheimer Disease: Remarkable Parallels
    If it takes years to die, it is not by an apoptotic mechanism. Klein and colleagues (2002) present an excellent model for this assertion and a couple of other phenomena that are present in Alzheimer disease (AD) and other neurodegenerative conditions. First, it shows how apoptotic death can be avoided in neurons that really do need to stick around (Raina et al., 2001). This phenomenon is remarkably similar to one we previously termed "abortosis" (Raina et al., 2001). Additionally, it provides a mechanism for how oxidative stress is proximal in the pathophysiology of AD (Nunomura et al., 2001) and by itself can lead to cell cycle re-entry in vulnerable neurons with subsequent arrest of the cell cycle program. Indeed, the combination of oxidative stress and cell cycle re-entry, in a "two-hit" manner, may be what bring forth the mature neurodegenerative phenotype in AD (Zhu et al., 2001). It will be exciting to see to what extent the Harlequin mutant mouse model parallels other aspects of neurodegenerative diseases.

    Arun K. Raina, George Perry, Xiongwei Zhu, and Mark A. Smith. Institute of Pathology, Case Western Reserve University, Cleveland, Ohio USA; mas21@po.cwru.edu

    References:

    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.

    Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. PubMed.

    Raina AK, Hochman A, Zhu X, Rottkamp CA, Nunomura A, Siedlak SL, Boux H, Castellani RJ, Perry G, Smith MA. Abortive apoptosis in Alzheimer's disease. Acta Neuropathol. 2001 Apr;101(4):305-10. PubMed.

    Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA. Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the 'two hit' hypothesis. Mech Ageing Dev. 2001 Dec;123(1):39-46. PubMed.

    View all comments by George Perry

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References

News Citations

  1. COX-2 in Neurodegeneration: Does It Wake Up a Sleeping Cell Cycle?

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Further Reading

Primary Papers

  1. 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.

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