BioWorld International Correspondent
LONDON A recent study has pinpointed genes that are dramatically down-regulated in Down’s syndrome, raising hopes that it may one day be possible to provide therapy to modify the course of the disease. Because all people with Down’s syndrome go on to develop Alzheimer’s disease, the findings also will be of intense interest to researchers in that area.
Sabine Bahn, clinical lecturer in psychiatry at the University of Cambridge in the UK, told BioWorld International, “Our discovery means that there is the potential to find drug targets for the treatment of both Down’s syndrome and Alzheimer’s disease. Although it may not be possible to treat fetuses with Down’s syndrome in utero, treatment after birth may still be able to ameliorate the development of the learning disability, and it may be possible to prevent or treat the later development of Alzheimer’s disease.”
Oxford BioMedica plc, a biotechnology company based in Oxford, UK, is negotiating terms, via the Babraham Institute in Cambridge (where Bahn is based for part of her time), for a potential collaboration to discover and validate new targets for the treatment of neurodegenerative disease. Chris Mundy, vice president of gene discovery at Oxford BioMedica, told BioWorld International, “I believe that this exciting work raises new opportunities for target discovery.”
Bahn, together with colleagues Michael Starkey at the UK Human Genome Mapping Project Resource Centre in Hinxton, UK, Piers Emson at the Babraham Institute and other collaborators, reports the results in the Jan. 26, 2002, issue of The Lancet in a paper titled: “Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down’s syndrome: a gene expression study.” The study was funded by the Birth Defect Foundation in the UK, the Wellcome Trust and the UK’s Biotechnology and Biological Sciences Research Council.
The cells of individuals with Down’s syndrome have an extra copy of chromosome 21. The syndrome affects about one in every 700 live births, but this figure varies according to the uptake of prenatal screening. People with Down’s syndrome have smaller brains than normal and all develop dementia resembling Alzheimer’s disease by the age of 30 to 40, possibly because they have three copies of the gene encoding the amyloid precursor protein, which plays an important role in the development of Alzheimer’s disease.
The study reported in The Lancet began because of Bahn’s interest in neurodevelopmental and neurodegenerative disorders including Alzheimer’s. Most people who develop Alzheimer’s, she reasoned, are elderly and have other pathological conditions such as heart disease and infections, which can lead to confounding changes in gene expression, which are unrelated to Alzheimer’s. So she decided to use stem cells from Down’s syndrome fetuses to provide her with a model system for people who would one day develop Alzheimer’s disease.
Her collaborators Clive Svendson and Maeve Caldwell at the UK Medical Research Council’s Cambridge Centre for Brain Repair supplied her with stem cells from Down’s syndrome fetuses and from normal fetuses. These were in the form of neurospheres balls of pluripotent neuronal stem cells that can be grown in vitro and have the capacity to differentiate further under the right conditions.
Bahn and her team extracted the messenger RNA from both populations of cells, cut it into fragments using restriction enzymes, labeled the fragments, and then ran the fragments on a gel. “There was one band in particular that was absent from the Down’s syndrome cells but strongly present in controls,” Bahn said.
They identified this gene as SCG10, which encodes a protein normally found in neurons, and which plays a role in their growth. “Interestingly,” Bahn said, “this gene had already been implicated as having a role in Alzheimer’s disease. Also, it is regulated by the transcription factor known as REST or NRSF which stands for neuron-restrictive silencer factor, a master regulator of neuronal gene expression. Its usual role is to suppress expression of neuronal genes in non-neuronal tissue.”
The researchers also decided to find out what would happen if they allowed the neurospheres to differentiate. Normally, if the cells are plated on a laminin surface and treated with suitable growth factors, about half develop into neurons and the rest into other types of nerve cell. “In the Down’s syndrome cells, we saw something really dramatic,” Bahn said. “There were hardly any neurons. We are now asking ourselves whether this is due to there being fewer progenitor cells present which develop into neurons, or whether the neurons that develop die quickly.”
Bahn’s next project is to explore further whether the lack of neurons that results when neurospheres from Down’s syndrome cells are allowed to differentiate is due to apoptosis or failure of neurogenesis. In collaboration with Lynda Sellers, also at the Babraham Institute, she will be looking for increases in the activity of genes known to be involved in the apoptosis cascade, using a custom-designed microarray comprising 600 cDNA sequences from genes whose products play a role in apoptosis.
She also wants to validate the results on cells from people with Alzheimer’s disease. “Our preliminary results show that SCG10 is significantly down-regulated in Alzheimer’s disease, but we want to check the other genes, too. If there is a common pathological pathway, then we must investigate it further.”