Finding a working ATM when you’re short of cash can be a life-saver. If you are a neuron, however, you may want to keep your ATM out of order because the currency it dishes out can be lethal. In today’s Neuron, researchers report that ATM, or ataxia-telangiectasia mutated protein, mediates cell cycle activation and subsequent death of neurons in response to DNA damage.
Neurons are postmitotic cells, so one wouldn't normally expect to find that they express cell cycle proteins. However, since the late 1990s, evidence has mounted that they not only express a plethora of such markers, but that such expression may be related to the neurodegeneration seen in a variety of diseases and conditions, such as Alzheimer's disease (AD) and stroke (see recent ARF Live Discussion for a comprehensive review of the evidence on this). This has lent credence to theories that attempted cell cycle reentry is disastrous for neurons and may be a major cause of neuronal apoptosis. Most recently, scientists have suggested that accumulated DNA damage may exacerbate cell cycle-related neurodegeneration (see recent ARF Live Discussion). Now, work by Mark Mattson and colleagues at the National Institute of Aging in Baltimore, Maryland, and elsewhere, seems to bolster that view.
First author Inna Kruman and coworkers tested the link between cell cycle reentry and DNA by comparing toxic compounds that damage the nucleic acid to others that don’t. As typical genotoxic agents, the authors used methothrexate and homocysteine, which cause uracil to incorporate itself into DNA (it belongs only in RNA), and etoposide, which inhibits the enzyme topoisomerase II and thus prevents the essential process of DNA untangling. To cause apoptosis without damaging DNA, Kruman used as control agents the protein phosphatase inhibitor staurosporine, and colchicine, which disrupts microtubules. (Kruman and Mattson have worked previously on the role of homocysteine in DNA repair and neurodegeneration; see ARF related news story.)
When Kruman and colleagues exposed cortical neurons to homocysteine, they noted a fourfold increase in the expression of the cell cycle protein Cdc25A. This was accompanied by an even greater increase in production of the tumor suppressor p53, which is known to be induced by DNA damage. In addition, the numbers of cells in the synthesis phase of the cell cycle were significantly higher in cultures treated with the genotoxic agents (approximately 20-fold for homocysteine and methothrexate, 35-fold for etoposide). In contrast, staurosporine led to more modest increases in Cdc25A (about twofold) and completely failed to nudge cells into S phase, as did colchicine. When the authors examined the DNA, they found that it sustained damage only in cells treated with the genotoxic agents, even though all treatments pushed about the same numbers of cells into apoptosis.
But does the DNA damage mediate apoptosis induced by the genotoxic compounds? To answer this question, Kruman and colleagues focused on the protein ATM, a kinase that is at least partly responsible for activating the cell cycle in response to DNA damage. When the authors pretreated the cortical neurons with the ATM inhibitors caffeine or wortmannin and exposed them to etoposide, the cells failed to enter S phase, even though DNA damage was just as evident as in cells treated with etoposide only. In addition, the cells did not become apoptotic.
For AD, in particular, this may be relevant because Mattson and colleagues found that cells treated with Aβ exhibited many of the symptoms of cells treated with etoposide, including increases in Cdc25A, S phase entry, and DNA damage. The authors also found that in cells lacking ATM, both Aβ and etoposide were much less potent at inducing apoptosis.—Tom Fagan
- The Cell Cycle and Alzheimer’s Disease—Let's Unite for Division!
- Are Neurons Just Too Laissez-Faire about Repair?
No Available Further Reading
- Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ, Emokpae R Jr, Gorospe M, Mattson MP. Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron. 2004 Feb 19;41(4):549-61. PubMed.