Newsdesk

652 http://neurology.thelancet.com Vol 5 August 2006

Results obtained by modelling variant Creutzfeldt-Jakob disease (vCJD) in mice transgenic for the human prion protein gene (PRNP) suggest that human PRNP codon129 heterozygotes could be more susceptible to infection with vCJD prions than with bovine spongiform encephalopathy prions. But, reports John Collinge’s group at the UK Medical Research Prion Unit in London, after infection with vCJD prions, these people may present with a neuropathological phenotype distinct from vCJD.

Since its appearance in the UK in 1995, 156 people have died from vCJD, a prion disease characterised by abundant fl orid prion protein (PrP) plaques and type 4 disease-related prion protein (PrPSc) in the brain. All the clinically recognised cases of vCJD have occurred in people homozygous for methionine at residue 129 (129MM) of human PrP, explains Jonathan

Wadsworth, a member of Collinge’s team, “which suggests that the MV and VV genotypes might be protective”.

Collinge and his colleagues previously reported that the neuropathological and molecular features of vCJD can be replicated by infecting mice homozygous for human PrP M129 with vCJD prions but that a distinct prion strain is propagated in V129 homozygotes. They now report what happens when 129MV heterozygote mice are infected with prions (PNAS 2006; published online June 29; DOI:10.1073/pnas.0604292103).

“What we found was quite surprising”, says Wadsworth. “After vCJD prion infection, all the 129MV mice had type 4 PrPSc in their brains but none of them developed clinical disease or the characteristic vCJD neuropathology.” In eff ect, continues Wadsworth, the 129MV heterozygote mice are carriers for vCJD prions, which means that

there could be a substantial number of symptom-free human carriers of these infectious agents. “We need to fi nd out if this is the case”, he says, “because these people could transmit vCJD prions through blood transfusions and other iatrogenic routes”.

“Extreme caution has to be exercised when extrapolating from animal models to people, but these fi ndings emphasise how important it is to continue research into prion diseases”, says Markus Glatzel (University of Hamburg, Germany). “No-one can predict what secondary transmission of vCJD will look like—we know that it has happened at least three times already—so we must continue to monitor the development of all human prion diseases and to examine the pathophysiology underlying these diseases.”

Jane Bradbury

Are there healthy human carriers for vCJD?

US researchers have developed a stem-cell protocol that encourages the growth of new motor neurons from the rat spinal cord that make functional neuromuscular junctions and provide partial recovery from limb paralysis (Ann Neurology 2006; published online June 26. DOI:10.1002/ana.20901). The work raises hopes that a similar strategy could be used to help people with nerve injuries or neurodegenerative disease.

“Embryonic stem cells retain the capacity to diff erentiate into any type of cell, and we can now coax them into becoming neurons”, explains team leader Douglas Kerr (Johns Hopkins University School of Medicine, Baltimore, MD, USA). “But even if you transplant such stem cells into a damaged nervous system, how do you get them to grow where you need them? And how do you overcome the inhibition to their growth from the

myelin on other neurons? These were the problems we hoped to overcome.”

Kerr’s team fi rst took mouse embryonic stem cells and treated them with retinoic acid and a chemical agonist of sonic hedgehog protein (HhAg1·3) to set them on the neurodiff erentiation path. They then transplanted some 60 000 of these cells—also treated with dibutyryl cyclic AMP (dbcAMP) and nerve growth factors to increase their survival and ability to grow axons—into the ventral grey matter of the spinal cord of rats paralysed by Sindbis virus infection-induced nerve damage.

“To overcome the eff ects of myelin inhibition we injected the rats daily with rolipram, a phosphodiesterase type-4 inhibitor found to have such properties in earlier studies”, explains Kerr.

Finally, the growing neurons were attracted down the sciatic nerve to the target muscles by placing a diff erent

type of stem cell secreting a motor axon tropic factor, GDNF, in the sciatic nerve.

“When all these conditions were met some 4100 new motor neurons were produced, and tests showed that 120 fi nally reached the muscles. This allowed the rats to partially recover from their paralysis; once again they could bear their own weight on the aff ected limb and take steps. We need to improve this, but these results are very encouraging.”

Rosario Sánchez Pernaute (Harvard University, Boston, MA, USA) remarked, “Kerr’s promising results emphasise the need for integrative combinatorial strategies in the development of restorative approaches for neurodegenerative disorders and the extraordinary value of embryonic stem cells for functional neuronal replacement therapies.”

Adrian Burton

Stem-cell protocol improves paralysis