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the efficiency of the PrPC to PrPres conversion.But, as the authors pointed out, both theexperimental conditions and the chaperonesthat were the most effective in the conversionprocess are not very relevant to the situationin vivo. What is important is the fact that thedifferent chaperones have an effect on thePrPC to PrPres conversion, probably due totheir ability to stabilize folding intermedi-ates.

The idea that a third party, such as a mol-ecular chaperone, might be involved in theconversion of proteins from their soluble toinsoluble states is intriguing (Fig. 1). Molec-ular chaperones interact with proteins thatare being synthesized, folded or translocatedinto organelles, as well as with mature pro-teins that tend to unfold (and so are prone toaggregation) because of environmentalinsults such as heat shock. Although the dif-ferent chaperones do not provide any directinformation for the folding process, theyseem to stabilize intermediates during fold-ing. By doing so, they act to reduce the num-ber of non-productive folding intermediatesthat might proceed to form intracellularaggregates.

Thus, we normally think of molecularchaperones as reducing protein aggregationinside the cell. But the possibility that a chaperone could feature in the conversionprocess is not so far-fetched. For example, if a chaperone-bound folding intermediate

(such as a protein rich in b-sheet) is releasedfrom the chaperone while in the vicinity ofan existing protein aggregate (that is, a‘seed’), the intermediate could conceivablybe recruited into the insoluble aggregate. In a similar way, certain isoforms of apo-lipoprotein E (a risk factor for Alzheimer’s disease) are thought to promote or stabilizeb-sheet conformations in amyloid-b pep-tide, thereby possibly facilitating the forma-tion of insoluble amyloid fibres5.

Intracellular accumulation of abnormal-ly folded proteins has a significant effect oncells — activation of the heat-shock/stressresponse. So might neurons harbouringamyloid deposits activate their stressresponse in an attempt to increase the levelsof molecular chaperones? A slight increase inthe levels of a cytosolic chaperone (hsp73)has been observed in neuronal cells express-ing PrPres, compared with their PrPC-expressing counterparts6. Perhaps moreinteresting was the fact that cells expressingPrPres, in contrast to cells making only PrPC,could not activate the heat-shock/stressresponse.

Why might this be? Perhaps the heat-shock response is activated as PrPres begins toaccumulate. If, over time, however, the chap-erones cannot re-fold or remove PrPres, thecells may then ‘turn off ’ their heat-shockresponse. Or perhaps infection results in atype of clonal selection — cells with analready attenuated heat-shock response arethe only ones able to propagate PrPres. If thatis the case, one wonders whether an attenuat-ed stress response might also be common toneuronal cells accumulating other abnor-mally folded proteins, such as those involved

Acommon feature of several neuro-degenerative disorders — includingAlzheimer’s and Parkinson’s diseases

— is a pathogenetic mechanism which issimilar to that proposed for prion diseases(Table 1). The proteins involved have poorlystructured native conformations that can bedestabilized further by genetic mutations,leading them to adopt b-sheet structures.These, in turn, result in the formation ofinsoluble, disease-causing protein aggre-gates in the brain. Under some conditionsthe aggregates can then act as a seed, inducing the normal protein to adopt theabnormal conformation1,2. But might theseapparent ‘errors in protein folding’ be medi-ated by other macromolecules? This obviousbut unresolved issue is addressed by twopapers3,4 from Lindquist and colleagues in Proceedings of the National Academy ofSciences.

The idea that a molecular chaperonemight participate in the conversion processseems plausible and has, in fact, been suggested for the prion-related disorders.Here, the apparent ‘species barrier’ (whereone species of animal is resistant to infec-tion by prions derived from anotherspecies) has led to the conclusion thatanother component must feature in theconversion of the normal prion protein,PrPC, into its infectious and pathologicalform, PrPres. Indeed, Prusiner and col-leagues2 have proposed that the conversionof PrPC to PrPres is facilitated by a host com-ponent, referred to as protein X.

Lindquist and colleagues have examinedthe interactions between various molecularchaperones and two prions — yeast Sup35and the mammalian prion protein. Sup35 is a translation termination factor that canexist in a soluble [psi–] form, or an aggregat-ed [PSI+] form which assembles into fibrilsresembling the prion protein in animals.Schirmer and Lindquist3 used circulardichroism to show a selective interactionbetween Sup35 and heat-shock protein(hsp)104. (Genetic studies have alreadyshown that this chaperone can influence thephysical state of Sup35 in vivo.) Over time,the hsp104–Sup35 mixture showed anincrease in light scattering, indicating thatone or both proteins were undergoing sometype of conformational change — most likely aggregation.

DebBurman et al.4 showed that yeasthsp104 and a second molecular chaperone,the bacterial GroEL protein (without its normal in vivo cofactor GroES), can interactwith the mammalian prion protein. More-over, both proteins promoted an increase in

Neurodegeneration

Chaperoning brain diseasesWilliam J. Welch and Pierluigi Gambetti

Figure 1 Relationships between protein folding, neurodegenerative diseases and ageing. Lindquistand colleagues3,4 have observed in vitro interactions between prion proteins and molecularchaperones. Might chaperones — either classical molecular chaperones or, perhaps, substrate-specific chaperones such as protein X, apolipoprotein E or presenilins — feature in the conversion ofprions, from their soluble to insoluble forms, through the stabilization of a certain foldingintermediate or intermediates?

Unfolded Intermediate Native

DiseaseDegradation Aggregation

Molecular

chaperone

Molecular

chaperone

Protein XApo E

Presenilins?

Molecularchaperone

Molecular

chaperone Ageing?

Table 1 ‘Aggregate-forming’ neurodegenerative diseases

Disease Protein Structure* Aggregate Location

Prion10 Prion a-helix and random coil b-pleated, protease Extracellularresistant and amyloid

Alzheimer’s5,11 Amyloid-b a-helix and random coil b-pleated and amyloid Extracellular

Parkinson's12–14 a-synuclein Imperfect repeats Lewy body, insoluble Cytoplasmic(b-pleated?)

Huntington's15 Huntingtin Trinucleotide repeats Insoluble (b-pleated?) Nuclear (intracytoplasmic?)

Spinocerebellar Ataxin 1 and 3 Trinucleotide repeats Insoluble (b-pleated?) Nuclearataxia 1 and3 (ref. 16)

*Refers to the dominant primary and secondary structure.

Nature © Macmillan Publishers Ltd 1998

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in the different neurodegenerative diseases.Moreover, because the stress response helpsto protect cells against a variety of metabolicinsults, could failure of the cells to activatethe stress response lead to increased neuronal vulnerability in response to othertraumas?

The accumulation of abnormally foldedproteins is also a hallmark of ageing. More-over, as cells age they lose their ability to acti-vate the stress response7,8. So might the neu-rodegenerative diseases that involve theaccumulation of abnormally folded proteinsbe a manifestation of ageing, with mutationsin particular gene products (Table 1) acceler-ating the process? Orgel presented9 a similarargument 35 years ago. In a strictly theoreti-cal paper, he suggested that the accumula-tion of protein-folding errors might help toexplain the phenomenon of ageing. In his‘error–catastrophe’ model, mistakes in pro-tein folding (especially of proteins involvedin protein-synthetic pathways) might initi-ate a type of self-perpetuation. As more mis-takes occurred in protein folding, theseerrors would lead to further errors such that,eventually, the cell would find itself awash inabnormally folded proteins. Perhaps evenmore prophetic was his suggestion that “spe-cial proteins might be synthesized which areconverted by a certain class of errors intolethal polypeptides”. Could the proteinsassociated with neurodegenerative disordersrepresent a type of ‘lethal polypeptide’?

All of the information about the molec-ular basis of what were thought to be differ-ent neurodegenerative diseases seems to be

culminating into a central theme — the con-version of soluble proteins into insolubleaggregates which, over time, give rise to neurodegenerative pathology. How theseprotein aggregates affect neuronal function,eventually leading to neurodegeneration, arejust some of the issues that now need to beaddressed.William J. Welch is in the Department of Surgery,Medicine and Physiology, University of Californiaat San Francisco, San Francisco, California 94143,USA. e-mail: welch@itsa.ucsf.eduPierluigi Gambetti is in the Division ofNeuropathology, Institute of Pathology, CaseWestern Reserve University, 2085 Adelbert Road,Cleveland, Ohio 44106, USA.e-mail: pxg13@po.cwru.edu1. Ghiso, J., Wisniewski, T. & Frangione, B. Mol. Neurobiol. 8,

49–64 (1994).

2. Paulson, H. L. et al. Neuron 19, 333–334 (1997).

3. Schirmer, E. C. & Lindquist, S. Proc. Natl Acad. Sci. USA 94,

13932–13937 (1997).

4. DebBurman, S. K. et al. Proc. Natl Acad. Sci. USA 94,

13938–13943 (1997).

5. Wisniewski, T., Ghiso, J. & Frangione, B. Neurobiol. Dis. 4,

313–328 (1997).

6. Tatzelt, J. et al. Proc. Natl Acad. Sci. USA 92, 2944–2948 (1995).

7. Liu, Y. C. et al. J. Biol. Chem. 264, 12037–12043 (1989).

8. Fargnoli, J. Proc. Natl Acad. Sci. USA 87, 846–850 (1990).

9. Orgel, L. E. Proc. Natl Acad. Sci. USA 49, 517–521 (1963).

10.Prusiner, S. B. Science 278, 245–251 (1997).

11.Frangione, B., Wisniewski, T., Castanol, E. M. & Ghiso, J. in

Research in Alzheimer’s Disease and Related Disorders (eds Iqbal,

K., Mortimer, J. A., Winblad, B. & Wisniewski, H. M.) 563–568

(Wiley, New York, 1995).

12.Polymeropoulos, M. H. et al. Science 276, 2045–2047 (1997).

13.Goedert, M. Nature 388, 232–234 (1997).

14.Nussbaum, R. L. & Polymeropoulos M. H. Hum. Mol. Genet. 6,

1687–1691 (1997).

15.Heinz, N. & Zoghbi, H. Nature Genet. 16, 325–327 (1997).

16.Ross, C. A. Neuron 19, 1147–1150 (1997).

If the density is less than critical, the cur-vature is negative, and the Universe willexpand eternally. This manifold is a three-hyperboloid — locally, a three-dimensionalanalogue of a saddle. This case is referred toas ‘open’ geometry, with infinite spaceimplicitly in mind. This is, however, a care-less term: a negatively curved space can be finite, as can a flat space, if it is multiplyconnected (see box).

The idea that the Universe may occupy amultiply-connected space is old3–6. Thestraightforward consequence would be thatour Galaxy, or galaxies familiar to us, wouldbe visible in many places, as if we were all in ahall of mirrors. In practice, however, obser-vations are obscured by the evolution of theobjects: the images of a single galaxy or clus-ter will look different, because the light hastravelled a different number of times aroundthe Universe and so the images have differentages. This effect is especially strong when thesize of space is of the order of the curvature,that is, it takes nearly the age of the Universefor light to travel all the way around.

But the topology of space also affects thefluctuations in the cosmic microwave back-ground, which originates from a time in theearly Universe when matter became too thinto trap radiation, at the ‘sphere of last scatter-ing’. These fluctuations should be evident ona wide range of angular scales, but finite spacewould mean that the spectrum of fluctuationsizes should cut off at a wavelength corre-sponding to the size of the space. Observa-tions7–9 by the COBE satellite are consistentwith an infinite Universe, or at least one larg-er than the ‘horizon’ (the sphere beyondwhich we cannot see, because light has takenthe age of the Universe to reach us from it).

But Cornish and collaborators1,2 notethat this is not true for a space with negativecurvature. In that case, large-angle micro-

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24 NATURE | VOL 392 | 5 MARCH 1998

Figure 1 A sphere intersects cubic domains. If theUniverse is smaller than the sphere of lastscattering (where the cosmic microwavebackground originates), these intersectionsshould be visible as circles of identicalmicrowave background fluctuation on the sky.

Our Universe occupies space. But whatsort of space? Mathematicians calldifferent types of space ‘manifolds’,

and characterize them by two properties: bythe local curvature — geometry; and theoverall shape — topology. Most cosmolo-gists are concerned only with the curvature,as it is directly related to the mass in the Uni-verse (and therefore it is observable), andbecause it determines the past and futureevolution of the Universe with time. Theglobal shape is not, in general, prescribed bygeometry, but it also is observable: topologi-cal information is imprinted on the fluctua-tions of the cosmic microwave background.This has already provided some evidencethat the Universe is infinite or, at least, notsmall compared with the distance we can see.But now Cornish, Spergel and Starkman1,2

have realized that the Universe can still befinite, and relatively small, if its curvature isnegative. Moreover, we may soon be able tomeasure its size and shape. This question of

whether the Universe is finite has profoundimplications for its birth.

Cosmologists classify the curvature of theUniverse as positive, zero or negative. Flat,euclidean space, called R3, has zero curvature— the sum of internal angles of a triangledrawn on it is 1807. With positive curvature, ason a sphere, the sum of the angles is more than1807, and with negative it is less. Einstein’sequation relates the curvature to the amountof mass present in the Universe (assumingthat the energy density of empty space — thecosmological constant — is zero). The sign ofthe curvature depends on whether the averagemass density at present is more than about2210−29 g cm–3, the critical density.

If the density has exactly this value, theUniverse is flat. If it is larger, the Universe hasa positive curvature — it is said to be ‘closed’.Space is then like the surface of a sphere, and the Universe will eventually collapse to infinite density in a Big Crunch. In this casethe Universe must be finite.

Cosmology

A circumscribed UniverseMasataka Fukugita

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