abundant in heart, liver and testis. Is thisbecause of the presence of other proteins inthe Diablo/Smac class in other tissues, or theexistence of tissue-specific apoptosis path-ways? IAPs may also act at the level of recep-tors for death signals9, so might Diablo/Smachave more regulatory targets?

These results also prompt interestingquestions about disease. Viruses, such asbaculovirus, may be able to extend the life ofinfected cells by expressing IAP proteins.Can cells in turn counteract viral infectionthrough Diablo/Smac? Cancer cells developby favouring proliferation over apoptosis as a result of alterations in several genes. Isloss of function of Diablo/Smac involved in the development and resistance to drugsof tumour cells? The recently identifiedDrosophila p53 protein controls apoptosis by regulating the expression of Reaper7,10.Vertebrate p53 is a well-known tumour suppressor. Might vertebrate p53 also in-duce apoptosis by controlling the expres-sion of Diablo/Smac or other, as yetunknown, functional analogues of Grim,Reaper and Hid?

The discovery of Diablo/Smac reveals theprocess of apoptosis at the level of the apop-tosome to be more complex than suspected,

but with a greater capacity for regulation.Sealing death-inducing proteins away in themitochondria offers one level of control.Then, the regulated release of these proteinsneeds to be accompanied by the formation ofa multiprotein complex — the apoptosome— whose propensity to induce death isantagonized by IAPs. Now we have the anti-antagonist, in the form of Diablo/Smac. Yetmore complexity may well exist. It seems thatthe cell has a greater say in its own destinythan we thought, and that scientists have yetmore opportunities for manipulating celldeath. ■

Vincenzo De Laurenzi and Gerry Melino are in theBiochemistry Laboratory, IDI-IRCCS, c/o theDepartment of Experimental Medicine, UniversityTor Vergata, 00133 Rome, Italy.e-mail: gerry.melino@uniroma2.it1. Verhagen, A. et al. Cell 102, 43–53 (2000).2. Du, C. et al. Cell 102, 33–42 (2000).3. Qin, H. et al. Nature 399, 549–557 (1999).4. Kumar, S. Cell Death Differ. 6, 1060–1066 (1999).5. Ekert, P. G., Silke, J. & Vaux, D. L. Cell Death Differ. 6, 1081–1086

(1999).6. Deveraux, Q. L., Takahashi, R., Salvesen, G. S. & Reed, J. C.

Nature 388, 300–304 (1997).7. Steller, H. Nature Cell Biol. 2, E100–E102 (2000).8. Wang, S. L., Hawkins, C. J., Yoo, S. J., Mueller, H. A. J. & Hay,

B. A. Cell 98, 453–463 (1999).9. Rothe, M. et al. Cell 83, 1243–1252 (1995).10.Brodsky, M. H. et al. Cell 101, 103–113 (2000).

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136 NATURE | VOL 406 | 13 JULY 2000 | www.nature.com

How can the long-term chemical evolu-tion of the Earth’s atmosphere be tracedthrough time? Samples of ‘fossil air’ are

available from some ice cores, but they pro-vide evidence for only the past 400,000 years.Longer-term records of atmospheric chem-istry must be sought in rocks that haveacquired some recognizable chemical signa-ture through interaction with the ancientatmosphere.

In the paper on page 176 of this issue, Baoet al.1 show that such a signature can befound in some sulphate rocks, which pre-serve a characteristic oxygen-isotope patternderived by atmospheric oxidation of sul-phur-bearing gases. This pattern derivesfrom atmospheric ozone; ozone is synthe-sized from oxygen, so the pattern may serveas a way to monitor atmospheric oxygen inthe past.

Variations in the abundance of stable isotopes of light elements such as hydrogen,carbon, nitrogen and oxygen are widelyused in geochemical and environmentalstudies. The isotopes act both as naturaltracers of the provenance of the materialsconcerned and as indicators of the con-ditions under which they formed or wereprocessed. These applications were first

introduced in 1947 by Harold C. Urey2, who showed how equilibrium and kineticchemical properties of isotopes depend linearly on differences in isotopic mass.

This linear dependence is so well established that geochemical studies using oxygen isotopes routinely use 18O/16O variationsonly, ignoring the redundant variations in17O/16O.

One striking departure from this linearmass-dependence occurs for the chemistryof ozone, as has been shown both in the labo-ratory3 and in the stratosphere4. In the syn-thesis of ozone from oxygen, both 17O and18O are enriched in the ozone by similarlylarge factors; the resulting ozone thereforecontains an apparent excess of 17O withrespect to the expected mass-dependentconcentration. By gas-phase exchange reac-tions, this 17O excess can be transferred toother atmospheric molecules such as CO2,CO, N2O, OH and so on5. Thus, various oxi-dizing trace-gas species in the atmosphereacquire an isotopic signature that distin-guishes them from components of the rest ofthe Earth.

What Bao et al.1 have shown is that somesulphur-bearing atmospheric compounds,specifically dimethyl sulphide from theoceans and sulphur dioxide from volcanoes,may be oxidized in the atmosphere. Theytherefore acquire the tell-tale excesses of 17O, which can then be incorporated into sulphate minerals in solid deposits on theEarth’s surface. The specific deposits theauthors analysed were soils derived from sulphate-rich rocks in the Namib Desert(Fig. 1), and volcanic ash-beds in the westernUnited States.

At this early stage, the observations ofexcess 17O in sulphate in soil and ash depositsyield only the qualitative conclusion that an atmospheric oxidation signature has beenpreserved in them. Further studies, exploit-ing 18O/16O fractionation and sulphur-isotope effects, will be necessary to establish

Atmospheric chemistry

Rock signature from the skyRobert N. Clayton

Figure 1 Fog over the Namib Desert. Bao et al.1 show that it is likely that an anomalous oxygen-isotope signature, generated in the atmosphere from ocean-produced dimethyl sulphide, has beenincorporated into the desert rocks. The result could provide the basis for a new approach to analysingthe chemistry of Earth’s ancient atmosphere.

NA

SA

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these results as the basis of a new quantitativetool for studying the chemistry of Earth’spast atmosphere.

Going beyond our own planet’s history,Bao et al. suggest that an analogous processmay occur on Mars. From the Viking andPathfinder analyses of Martian soil and dust,it is known that these materials contain up to about 2.5% sulphur, a high value that suggests they are derived from volcanic gases that were deposited from the atmos-phere. So oxygen and sulphur in sulphatesfrom so-called SNC meteorites (which are of

presumed martian origin), and from futuresamples returned from Mars, may provideinformation about the chemical evolutionof the martian atmosphere. ■

Robert N. Clayton is in the Enrico Fermi Institute,University of Chicago, 5640 South Ellis Avenue,Chicago, Illinois 60637-1433, USA.e-mail: r-clayton@uchicago.edu1. Bao, H. et al. Nature 406, 176–178 (2000).

2. Urey, H. C. J. Chem. Soc. 562–581 (1947).

3. Thiemens, M. H. & Heidenreich, J. E. Science 219, 1073–1075

(1983).

4. Mauersberger, K. Geophys. Res. Lett. 8, 935–937 (1981).

5. Thiemens, M. H. Science 283, 341–345 (1999).

It is a rare and fortunate individual who has not witnessed the devastating conse-quences of neurodegenerative illness. This

experience may have come from seeing theinexorable deterioration of a family membersuffering late in life from Alzheimer’s orParkinson’s disease, the sudden loss of motorfunction in patients in the prime of life suf-fering from amyotrophic lateral sclerosis(also known as Lou Gehrig’s disease), or thetragic consequences of any of the other dis-eases that wreak havoc in the nervous system.Attempts to understand the neuronal deathunderlying these disorders have been com-plicated by their varying times of onset andclinical courses. Might the loss of neurons inall of these diseases follow a common prin-ciple? Or does the neuronal death in eachhave its own rules and regulations? On page195 of this issue1, Clarke and colleaguesprovide experimental evidence to support a common, ‘one-hit’ model of cell death inneurodegenerative diseases that has impli-cations for treatment strategies.

The genes that are mutated in neuro-degenerative diseases in humans and experi-mental animals are being identified rapidly,and in vitro and in vivo analyses are unravel-ling the functions of the protein products of these genes. These studies have led to the classification of neurodegenerative dis-eases according to the biochemical mecha-nisms of the mutant gene products. Thus, the‘polyglutamine diseases’ and ‘protein-aggre-gation disorders’, including Alzheimer’s andParkinson’s diseases, are characterized by theaccumulation of aggregates of abnormallyfolded peptides or proteins. In the ‘axon-opathies’, such as amyotrophic lateral sclero-sis, alterations in the morphology of neu-ronal axons and in the expression of genesencoding neurofilaments (part of a neuron’scytoskeleton) appear. And the ‘ion channel-opathies’ show perturbations in the flux ofions across the neuronal membrane2–6.

So there are obvious differences in thebiochemical pathways that are altered in dif-ferent neurodegenerative diseases. Despitethis, it has been suggested that the neuronaldeath in all of these disorders might occuraccording to a common principle. One suchtheory that has been proposed is the ‘cumu-lative-damage’ hypothesis, which holds thatthe accumulation of macromolecular dam-age or a toxic substance over time leads to theeventual demise of the affected neuronalpopulation (see references in ref. 1). Alterna-tively, cell death might result from defects in neuronal metabolic balance as a conse-quence of aberrant signalling7.

The cumulative-damage hypothesis pre-dicts that the probability of cell death in the affected neurons will increase over time.This translates into a sigmoidal decline incell number over time. So, early in the dis-ease, few cells have accumulated enough ofthe toxic product or enough damage to trigger cell death, and few cells die. Late in disease progression, most neurons have accumulated sufficient toxic product,resulting in a large increase in the rate of cell death.

If the cumulative-damage theory doesnot hold, however, one would expect theprobability of cell death to either remainconstant or decline over time. This wouldtranslate to an exponential decline in cellnumber as the disease progresses. For exam-ple, if half of the cells in the affected structuredie each year, then, after the first year, half of the cells would remain; after year two, aquarter would remain; and so on. To distin-guish between these two possibilities for aspecific disease, one need simply measurethe rate of cell loss over time to determinewhether it conforms to a sigmoidal or anexponential decline. No knowledge of thebiochemical mechanism initiating cell loss,or of the specific cell-death pathway active in the dying cells, is required.

Clarke et al.1 have used this prediction to test and exclude the cumulative-damagehypothesis for a broad spectrum of neuro-degenerative conditions. These include 12different models of photoreceptor degen-eration, ‘excitotoxic’ cell death in vitro, loss of cerebellar granule cells in a mouse model,and Parkinson’s and Huntington’s diseases.In this range of diseases, five different neuronal types are affected. The differentdisorders result from mutations that causediffering biochemical alterations in the cell,and occur in both the neurons affecteddirectly by the mutations and those dying asa consequence of the initial cell deaths. Thedata were collected in the authors’ laborato-ries or taken from independent publishedstudies of the kinetics of cell loss in specificneurodegenerative situations.

In each of these cases, the rate of cell deathis best fit by an exponential decay, arguingagainst models in which the accumulation of damage or build-up of a toxic substancedetermines the rate of cell loss. Clarke et al.1

propose instead that affected neurons are in an abnormal state (which they call the“mutant steady state”) in which there is anincreased probability that a “single rare cata-strophic event” will lead to cell death. Thisone-hit model of cell loss may be common tomany forms of neurodegeneration. Thishypothesis does not require the biochemicalmechanisms participating in cell loss to bedefined, nor does it dictate the mechanismby which the neurons die. But a specific cell-death process called apoptosis is importantin many of the diseases studied, including theretinal degeneration models, death of cere-bellar granule cells in response to beingdeprived of the proper neuronal targets8, andexcitotoxic cell death in vitro and in vivo9.Although the evidence for a role of apoptosisin Parkinson’s and Huntington’s diseases isless clear, the single rare catastrophic event in all of these diseases could well be the irreversible commitment of single cells to the apoptotic death cascade7.

This elegant study1 also has implicationsfor therapeutic intervention. As discussed bythe authors, the fact that the probability ofcell death in the affected population is eitherconstant or decreases during disease pro-gression means that the chance that a neuroncan be rescued from death by pharmacologi-cal intervention does not decrease with age.However, in some well-characterized animalmodels of neurological disease, obvious his-tological abnormalities appear and deterio-ration of neuronal function occurs well inadvance of cell loss1. It would be interestingto find out whether the one-hit hypothesis isrelevant in these models, despite the discor-dance between the progression of symptomsand neuronal death. Nonetheless, theseresults are certain to stimulate much debateand experimentation, aimed both at identi-fying common mechanisms of neurodegen-

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NATURE | VOL 406 | 13 JULY 2000 | www.nature.com 137

Neurodegeneration

One-hit neuronal deathNathaniel Heintz

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