whether and how the inclusions contributedirectly to the disease process.

The debate has had especial intensitywhere polyglutamine diseases,and Hunting-ton’s disease in particular, are concerned2,3.For the polyglutamine diseases, inclusionbodies containing mutant protein sprang topublic attention in a series of papers2–5 thatappeared in 1997. In the case of Hunting-ton’s disease, the critical protein is calledhuntingtin (htt), and inclusions containingmutant htt are found at the major site ofneurodegeneration, the medium spiny neu-rons in a brain region called the striatum.

Depending on the system and the manip-ulations performed,over the years the exper-imental evidence has been interpreted asshowing that the inclusion bodies cause dis-ease, protect against disease, or are simplyincidental6.The largest contingents are thosewho believe that inclusions are the majorpathogenic species, owing to their ability toabsorb other critical cellular proteins, andthose who feel inclusions are protective, inthat they sequester mutant protein out ofharm’s way. Resolution of this issue is nec-essary for many reasons, not least becausemany current studies aim to interfere withinclusion-body formation as a potentialtreatment for Huntington’s disease and theother neurodegenerative disorders charac-terized by protein aggregates7.

Arrasate and colleagues1 have devised anelegant real-time technique for assessing thefactors that affect the risk of neuron death in culture. They used a common model of

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Huntington’s disease in which striatal neu-rons are transiently transfected with a patho-genic fragment of mutant htt (htt-exon1).They developed an automated microscopicsystem to simultaneously follow inclusion-body formation, the presence of diffuse httand cell survival in the same neuron over aperiod of days. To visualize deposition ofhtt in transfected cells, they employed a con-struct of htt-exon1 fused with green fluores-cent protein. As expected, inclusion bodiesformed (Fig. 1), in the nucleus and in thecytoplasm,and neurons died.

To begin with, Arrasate et al. performed amathematical analysis of the risk of death — asort of actuarial assessment in tissue culture.From this analysis, they reached two conclu-sions. First, the risk of dying was low in neu-rons that had been transfected with a control(non-pathogenic) form of htt-exon1 andhigh in cells expressing htt-exon1 with anexpanded polyglutamine tract; furthermore,the risk increased with increasing size of themutant polyglutamine stretch. Second, theyfound that the risk of death in cells withmutant htt-exon1 was linear over time;that is,risk seemed to be largely time-independent.

So, what variables affected the risk of celldeath? Not unexpectedly, inclusion bodieswere one such variable. Importantly, thebasic features of inclusion-body formation— size and growth with time — in this modelsystem accurately replicated the picture seenin Huntington’s disease. By following thesame neuron over time, Arrasate et al. foundthat cells that failed to form inclusion bodies

Neuron protection agencyHarry T. Orr

The results of an innovative way of tracing the life and death of neurons inculture favour one side of a debate about the protein accumulationsassociated with certain disorders of the nervous system.

On page 805 of this issue, Arrasate and colleagues1 show that clumps of mutant protein, seen in certain

neurons and characteristic of Huntington’sdisease, reduce the chance that the neuronswill die — at least in culture. So, why is this worth noting? The answers lie in theingenious manner in which the investi-gators made their observations, and becausethey address a point of fervent debateamong those studying many human neuro-degenerative diseases, including Hunting-ton’s disease.

Neuropathologists have long known thatsome disorders are characterized by anabnormal accumulation of macromoleculesinside cells. These ‘inclusion bodies’ arefound, for example, in the brains of patientssuffering from Alzheimer’s disease, priondiseases, amyotrophic lateral sclerosis (alsoknown as Lou Gehrig’s disease), Parkinson’sdisease, and a group of nine so-called poly-glutamine diseases, of which Huntington’sdisease is the most widely known. The com-mon factor in polyglutamine diseases is agenetic mutation that produces abnormalrepeats of the amino-acid glutamine in theencoded protein, with more repeats beingmore pathogenic.

With the advent of studies by moleculargeneticists and cell biologists, it became clearthat, in the inherited forms of each of thesediseases, inclusion bodies contain the pro-tein encoded by the gene containing the disease-causing mutation. These observa-tions reignited long-standing questions of

Figure 1 Picture of health? This image, produced by Arrasate et al.1,shows a striatal neuron (yellow) that has been transfected with the disease-associated version of huntingtin, the protein that causesHuntington’s disease. The orange–red structure is an inclusion body.

Arrasate et al. show that transfected neurons that form such bodies livelonger than those that do not. Nuclei of untransfected neurons (blue) are seen in the background, along with projections from other neurons (green).

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‘ingredients’, the nucleus would becomeunbound. The transition from bound tounbound neutron-rich nuclei occurs at theso-called neutron drip-line,which marks theboundary of the existence of nuclei (Fig. 1).

For the examples of helium and nitrogen,the drip-line isotopes are 8He and 23N. Theseand other neutron-rich nuclei are not foundon Earth because they undergo �-decay,in which a neutron is transformed into a proton, improving the balance between neutrons and protons.

Nuclei close to the neutron drip-line canhave one or two extremely weakly boundneutrons. The energy required to separatethe two weakly bound neutrons from 6He is only 0.973 MeV (megaelectronvolts),compared with typically 8 MeV to remove a single neutron from a stable nucleus. The low binding energy of these neutrons resultsin quantum-mechanical tunnelling to largedistances, allowing their wavefunctions (orprobability distributions) to extend wellbeyond the tightly bound core, forming a diffuse neutron cloud or halo (Fig.1).

The effect that this halo might have onnuclear fusion has been the subject of somecontroversy. Because the nuclear force has ashort range, the attractive force between twonuclei is closely related to the degree of over-lap of their matter distributions. The poten-tial barrier (fusion barrier), which must beovercome in fusion,occurs at the radial sepa-ration where this force balances the repulsiveCoulomb force between the positivelycharged protons in the two colliding nuclei.According to this picture, the neutron halomight be expected to contribute a longer-range attractive force, which would reducethe energy of the fusion barrier. Further-more, in reactions between stable nuclei,the likelihood of fusion occurring is knownto be enhanced at energies well below thefusion barrier if the transfer of one or more

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had an increased risk of death, indicatingthat the inclusion body is not required forpolyglutamine-induced neuronal death.Remarkably, when neurons expressing equallevels of mutant htt-exon1 were followedindividually, those neurons in which inclu-sion bodies formed had a significantlyreduced risk of dying compared with neu-rons in which mutant htt-exon1 remaineddiffuse. Moreover, inclusion-body forma-tion reduced the amount of diffuse mutanthtt elsewhere in the neuron.

So inclusion-body formation actuallyprolonged survival and protected neurons,seemingly by reducing the amount of a toxic,diffusely distributed form of mutant htt. Butalthough the results provide compelling evidence that readily visible (1 �m2),mutantpolyglutamine inclusion bodies are protec-tive,and not pathogenic, they do not rule outthe possibility that the major toxic species arethe early precursors to inclusion bodies —

typically referred to as microaggregates.The long-term strength of this study1 lies

in the approach itself: the ability to find outwhether a cellular feature of a disease is pathogenic, beneficial or merely incidentalwill help greatly in understanding diseasemechanisms. It will also be interesting to see whether the results end the debate on the pathogenic role of inclusion bodies in polyglutamine diseases. If they don’t, onewonders what would. ■

Harry T. Orr is at the Institute of Human Genetics,University of Minnesota, 516 Delaware St SE,Minneapolis, Minnesota 55455-0374, USA.e-mail: harry@lenti.med.umn.edu

1. Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R. &

Finkbeiner, S. Nature 431, 805–810 (2004).

2. Davies, S. W. et al. Cell 90, 537–548 (1997).

3. Paulson, H. L. et al. Neuron 19, 333–344 (1997).

4. Skinner, P. J. Nature 389, 971–974 (1997).

5. DiFiglia, M. et al. Science 277, 1990–1993 (1997).

6. Sisodia, S. S. Cell 95, 1–4 (1998).

7. Ross, C. A. & Poirier, M. A. Nature Med. 10, S10–S17 (2004).

Nuclear physics

Neutron halo slipsDavid Hinde and Mahananda Dasgupta

In neutron-rich nuclei, weakly bound neutrons form a halo surroundinga compact core. Unexpectedly, it seems that this halo does notimprove the chances of the nucleus fusing with another nucleus.

A ccelerator facilities that can supplybeams of highly unstable, radioactiveisotopes are making it possible to

study nuclear reactions that occur naturallyonly in violent cosmic events such as super-novae, but which determine many of the ele-mental and isotopic abundances found onEarth. Some of the most neutron-rich ofthese nuclei have a diffuse neutron cloud that extends to large distances beyond thecompact nuclear core. Based on the lessonslearned from the fusion of stable nuclei, thishalo might be expected to enhance, manytimes over, the probability of nuclear fusionat low energies.But,on page 823 of this issue,Raabe and colleagues1 describe an ingeniousmeasurement that shows no such enhance-ment, indicating that the behaviour of theneutron halo is more unusual than expected.

Atomic nuclei, which are made up ofprotons and neutrons, exist because ofthe attractive nuclear force between theirconstituents. This force depends on manyvariables, but in particular favours equalnumbers of protons and neutrons. Thus,for example, the most common isotopes ofthe elements helium and nitrogen, havingtwo and seven protons respectively, are 4Heand 14N. If more neutrons were added to anucleus, either one by one, or in pairs, thenucleus would become less strongly bound.Eventually, at the point where the energy ofthe new nucleus is greater than that of its

Stablenucleus

Distance from centre

Den

sity

Den

sity

Pro

ton

num

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, Z

Neutronhalo

Distance from centre

N = Z

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Neutron number, N8

8

28

28

50

50

82

82

126

Figure 1 Nuclear stability and neutron halos. In stable nuclei, the number of neutrons tends to exceedthe number of protons. Nuclei with too many neutrons, however, are unstable; beyond the ‘neutrondrip-line’, nuclei become unbound. Isotopes close to this line may have one or two neutrons that areweakly bound to the core nucleus. Through quantum-mechanical tunnelling, and because theirbinding energy is low, these neutrons form a nuclear halo: the neutron density extends to greaterdistances (inset, right) than is the case in a well-bound, stable nucleus (inset, left). According to Raabe et al.1, the existence of this neutron halo does not make it any more likely that the nucleus will undergo fusion.

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