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396 http://neurology.thelancet.com Vol 4 July 2005

Accumulation of mutant huntingtin(mhtt) in different types of brain neu-rons may be a necessary step in theonset of neuropathological symptomsin Huntington’s disease (HD; Neuron2005; 46: 433–44). Interactions bet-ween different cells could therefore beneeded for HD—and perhaps other neu-rodegenerative diseases—to develop.

HD is one of nine neurodegenerativedisorders in which neurons and othercells express mutant proteins with an

expanded CAG repeat encoding apolyglutamine tract. Although theaccumulation of toxic polyglutamineproteins seems to be involved in disease pathogenesis, researchers arenot sure how.

“It’s possible that these proteinscause ‘cell-autonomous’ toxicity thateventually leads to disease”, explainsstudy leader William Yang, (Neuro-psychiatric Institute at UCLA, California,USA), “but a second theory suggests

pathological interactions between cellsmay be needed. There is evidence thatsuch interactions do occur, perhapsleading to interference in transcription,the blocking of vesicular transport, orthe appearance of alterations inastrocytes and microglia in affectedbrain regions. Till now, however, theevidence for such pathogenicinteractions was limited.”

Yang’s team produced two types ofconditional HD mice. Both accumulated

Cell–cell interactions may be crucial in HD

Korean and US scientists have, for thefirst time, developed embryonic stem-cells (ESCs) genetically identical topatients—of both sexes and a range ofages—by transfer of skin-cell nuclei intodonated oocytes. The researchers wereable to develop ESCs with a reliabilityand efficiency an order of magnitudegreater than previously achieved.

The team, led by Woo Suk Hwang(Seoul National University, Korea),attempted to develop ESC linesgenetically identical to 11 individuals(nine with spinal-cord injury, one withjuvenile diabetes, and one with congenital hypogammaglobulinaemia)by transferring nuclear DNA intoenucleated oocytes. The group hadpreviously developed ESCs by auto-logous transfer, in which nuclear DNAfrom a woman is introduced into her

own egg. In their most recent research,Hwang and colleagues generatedsuccessfully 11 cell lines from nine ofthe 11 patients using oocytes fromgenetically distinct individuals (Science2005; published online May 19,DOI:10.1126/science.1112286).

Coauthor Gerald Schatten (Universityof Pittsburgh School of Medicine, PA,USA) explains that his team’s findingshave immediate application in theproduction of “diseased human ESCsfrom patients with specific illnesses (eg, schizophrenia and autism) forwhich we don’t yet understand themechanism—so that mechanistic,genetic, or environmental determi-nants can be discovered”. Schatten alsopoints out the importance of these cellsbeing grown on human feeder cells.Systems previously used to culturehuman ESCs have used feeder cellsfrom other mammals to supportgrowth, which throws doubt on theresults of research of human disordersin these cells; Hwang and colleagues’cell lines were supported by feeder cellsfrom either the nuclear DNA donor or agenetically unrelated individual.

Stephen Minger (Kings CollegeLondon, UK), who has closelyfollowed the research since theKorean group announced theproduction of the first human ESClines by autologous transfer a littleover a year ago, describes the research

as stunning. “We didn’t think thatthey would progress so quickly in 5 or 10 years, let alone a year.”Minger, who has visited Hwang’s lab,explains that the researchers havebeen able to progress so rapidlybecause they do more than 1000nuclear transfers a day, mostly onanimal cells, to perfect the technique.The team’s cell lines developed byautologous transfer took around250 tries, the 11 cells lines generatedin the present study took on averageless than 20.

The great expectations for thetherapeutic applications of humanESCs will likely take some time torealise. Schatten explains that the nextstep will be to study directeddifferentiation into tissue-specificprecursors or therapeutic cells (such asdopaminergic neurons for Parkinson’sdisease). These cells would have to beextensively and rigorously tested inanimals for safety and efficacy beforeinvestigations in human beings couldeven be contemplated.

“I wouldn’t overhype it in terms oftherapeutic value”, agrees Minger,“but as for setting the standards ofscientific expertise this research ismagnificent”. Minger hopes thatinternational collaboration will enableother groups to replicate these results.

Peter Hayward

Stunning progress in stem-cell research

Hwang’s team’s announcement has attracted global media attention

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similar amounts of mhtt protein, but indifferent places: one in corticalpyramidal neurons only (corticalmodel), the other in all types of neurons(pan-neuronal model). “If cell–cellinteraction is needed, then the miceproducing mhtt in the pyramidalneurons only should not go on todevelop HD-like symptoms in thesecells”, explains Yang.

At 6 months, pan-neuronal animalshad begun to show HD-like motordeficits that deteriorated over time. Thecortical-model mice, however, showedno such problems. Furthermore, thepan-neuronal mice had nine times morereactive gliosis than their wild-typelittermates, yet no differences wereseen between the wild-type mice andthe cortical-model mice. “This stronglysuggests that reactive gliosis arose as aconsequence of non-pyramidalneuronal dysfunction”, explains Yang.

Electron micrographs showed ultra-structural signs of neurodegeneration

in pan-neuronal mice at 1 year, whereasonly very early signs were seen in theircortical-model counterparts. “Indeed,our results suggest that without dys-function in cortical interneurons orsubcortical neurons, little pathogenesisoccurs within the cortical pyramidalneurons”, says Yang. “When we testedwhat interactions might be involved,we found that GABAergic inhibitoryinput to the cortical pyramidal neuronswas reduced early in the pan-neuronalmodel, but not in the cortical model. Itwould seem, therefore, that simpleaccumulation of mhtt in one of theaffected cell types alone—in this case,cortical pyramidal neurons—is in-sufficient for HD symptoms to developin these neurons. Cell–cell interactionsseem to be needed.”

“One immediately wonders whetherother polyglutamine diseases mightrequire similar cell–cell interactions”,remarked José Lucas (CSIC/UniversidadAutónoma, Madrid, Spain). “Much

more research is needed to understandwhat the range of these interactionsmight be, at what time in life they beginto occur, and how they might differbetween diseases. But if suchinteractions are gradually revealed, newtherapeutic and preventive optionscould become available.”

Adrian Burton

http://neurology.thelancet.com Vol 4 July 2005 397

Scientists have watched rogue prionsinvade and travel through neurons. Thefinding should bolster efforts tounderstand how the disease-causingproteins damage the brain, and may aidthe development of new treatments.

Abnormal prion proteins causetransmissible spongiform encephalo-pathies (TSEs), which include scrapie insheep, mad cow disease in cattle, andCreutzfeldt-Jacob disease (CJD) inhuman beings. The degenerative braindiseases can occur when foodcontaminated with rogue prions iseaten. The proteins then make theirway from the periphery to the brainwhere they convert healthy host prionproteins into their rogue form.

“It’s critical to know how neuronspick up this infectious material”, saysByron Caughey (National Institutes ofHealth, Hamilton, Montana, USA), “andhow it spreads.”

Caughey’s team labelled aggregatesof rogue prion proteins with a

fluorescent dye and used them to infectcultures of hamster and mouse braincells (J Neurosci 2005; 25: 5207–16). Byuse of confocal microscopy, theywatched as small pieces of theinfectious aggregate were pulled insidethe cell into tiny membrane-bound sacscalled endosomes. The vesicles thensped along the cells’ processes andcongregated at their ends close toneighbouring cells.

Very occasionally the team sawaggregates of fluorescently taggedprions pass from one cell to the next.This may be happening more oftenthan we can see, speculates Caughey,because the aggregates may be toosmall to visualise.

This low occurrence of infection mayexplain the low incidence of TSEs, saysMarkus Glatzel (University of Zurich,Switzerland). Although millions ofBritish people may have eaten prion-infected beef, only 129 cases of variantCJD have been reported.

Caughey’s team used the samefluorescent tag to label non-infectiousprion proteins and amyloid �, a keyplaque forming protein in Alzheimer’sdisease. When the labelled proteinswere added to brain cultures, they toobecame internalised and moved aroundthe cells like the infectious prions.

“It seems that the infectious prionprotein piggy backs on a normalphysiological trafficking pathway”,says Caughey, and that a similartrafficking process occurs inAlzheimer’s disease. Drugs that blockspecific components of this pathwaymay prove therapeutic. For example,compounds that alter endosome pHmay affect prion infectivity.

The next step is to see if a similarprocess occurs in vivo, although thismay prove problematic becausevisualising labelled proteins in the livingbrain is difficult.

Helen Pilcher

Rogue prions caught in action

Pyramidal (orange) and cortical interneurons (blue)

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