For personal use. Only reproduce with permission from The Lancet.

THE LANCET Neurology Vol 2 November 2003 http://neurology.thelancet.com 651

Newsdesk

Expansion of a CAG repeat in thehuntingtin gene—which is translatedinto a polyglutamine tract in thehuntingtin protein—is known to causeHuntington’s disease (HD) in humanbeings. But until recently, just how themutated protein has its toxic effect hasbeen unknown. Now, two researchgroups have shown that mutanthuntingtin protein containing anexpanded polyglutamine tract blocksfast axonal transport. “Since axonaltransport is critical to neuronalviability and function, this findingcould both enhance our under-standing of disease mechanisms as well as open up new therapeuticapproaches to these diseases”,comments Larry Goldstein (HowardHughes Medical Institute, Universityof California, San Diego, CA, USA),lead author on one of the two paperspublished in Neuron.

Goldstein and co-workers showedthat a reduction of normal huntingtinexpression—or expression of a humanhuntingtin protein containing an

expanded polyglutamine tract—inDrosophila melanogaster larvaedisrupted axonal transport in neurons(Neuron 2003; 40: 25–40). Theseresearchers went on to investigate theinfluence of expanded polyglutaminetracts in several different proteins andfound that all caused axonal transportdefects and apoptotic neuronal celldeath.

In a separate study, Scott Brady andcolleagues (University of Illinois,Chicago, IL, USA) showed that mutatedhuman huntingtin reduced bothanterograde and retrograde axonaltransport in the giant axon of the squid.Brady’s group found that these effectswere not confined to huntingtin asexpanded polyglutamine tracts in the androgen receptor protein alsoinhibited fast axonal transport in thesquid axoplasm and inhibited neuriteoutgrowth in a neuroblastoma cell line(Neuron 2003; 40: 41–52).

The results of these two studies mayhelp to answer some of the questionsthat have perplexed researchers. For

example, why are neurons preferentiallyaffected in HD and why do they dielater in life after decades of apparentlynormal function? “Neurons areuniquely dependent on fast axonaltransport for their survival”, explainsBrady, “so they will be most vulnerableto decrements in fast axonal transport.”And since the speed of axonal transportand the amount of material that can betransported declines as we get older, thismay explain the onset of polyglutaminediseases, such as HD, later in life.

“These two papers in Neuron arehighly significant because they extendthe concept of neurodegenerativedisease caused by impaired axonaltransport from more commondisorders, such as Alzheimer’s disease,to polyglutamine diseases, with theimplication that multiple neuro-degenerative diseases may share asimilar mechanism”, John Trojanowski(University of Pennsylvania School ofMedicine, Philadelphia, PA, USA) toldThe Lancet Neurology.Rebecca Love

Huntingtin halts axonal transport

A new, fast, and efficient coculturemethod for the conversion of mouseembryonic stem (ES) cells into neurons in vitro has been reported byresearchers led by Lorenz Studer of theMemorial Sloan-Kettering CancerCenter (NY, USA). As well as definingthe conditions needed to direct ES cellsto become neural stem cells, astrocytes,oligodendrocytes, or neurons, the teamhas also selectively generated forebrainGABAergic neurons from ES cells,something that has not been achieved before. “We have alsosuccessfully transplanted ES cell-derived dopaminergic neurons intomice with experimentally inducedParkinson’s disease and demonstratedrobust alleviation of the behaviouraldeficits in those mice”, adds Studer.

ES cells derived from fertilisationand nuclear transfer (ntES) differen-tiated into dopaminergic neuronsunder specific culture conditions. Thecells were tested for neurotransmitter

production, harvested, and injected intothe denervated striatum of mice thathad lost around 70% of their midbraindopaminergic neurons after lesioningwith 6-hydroxydopamine. 2 monthsafter transplantation, the grafts hadextended over a large portion of thestriatum, but had not crossed into thecortex. Behavioural tests done beforethe transplant and up to 8 weeks aftershowed that mice had recovered morethan 70% of their motor function (Nat Biotech 2003; 21: 1200–07).

“This is an extremely importantstudy in this field: Studer demonstratesthat ntES cells, and also the more‘classical’ ES cell lines, can be pushedinto guided differentiation in a veryreproducible and homogenous way”,comments Marc Peschanski (Faculte deMedecine, INSERM, Paris, France).“This is definitely new for non-genetically modified cells.” The use ofES cells for cell therapy in variousneurodegenerative diseases is not

beyond reach, he adds, because thechallenges that remain should besurmountable with the techniques andtools that Studer’s group and othersalready possess. Pilot clinical trials mayonly be 5 years away, Peschanskipredicts, but he also warns that a lot ofwork still has to be done to ensure cellstability after transplantation and toinvestigate the need for a “suicide” genethat could be triggered if abnormalproliferation were to occur. The risk ofteratoma—a major drawback inprevious experiments with implantedES cells—seems to have been overcomeby Studer’s group and Ron McKay’sgroup, who studied Nurr-1 expressingcells (Nature 2002; 418: 50–56).“Defining risk control and working outthe surgical procedures that mayeventually be used in patients will makelong-term studies in non-humanprimates unavoidable”, concludesPeschanski.Kathryn Senior

Therapeutic cloning works in mouse model of Parkinson’s disease