The UK-based Motor Neurone Disease Association has recently funded a £800,000 ($1.2 million) program to study motor neurons derived from the skin cells of amyotrophic lateral sclerosis (ALS) patients with rare, disease-causing mutations in the gene TARBP. Although the mutations are thought to cause only a tiny fraction of cases, abnormalities in the gene’s protein product, called TDP-43, are observed in up to 90 per cent of cases and in other neurodegenerative diseases like dementia. Detailing the mutations’ effects might shed light on common processes underlying neurodegeneration.
The research team, which includes Siddharthan Chandran and Sir Ian Wilmut from the University of Edinburgh, Christopher Shaw from King’s College London in and Tom Maniatis from Columbia University in New York, will generate induced pluripotent stem (iPS) cells from skin fibroblasts isolated from patients with the mutations and from healthy individuals without. They’ll then differentiate the iPS cells into motor neurons, which degenerate in ALS, or support cells called astrocytes, which are thought to play a role in the spread of the disease throughout the brain and spinal cord. By culturing motor neurons and astrocytes together in a series of ‘mix and match experiments’ (in which healthy motor neurons will be cultured with astrocytes harbouring mutations and vice versa), the researchers hope to better understand how the mutations affect interactions between the two cell-types.
“Bringing together the genetic revolution of the last decade with the spectacular progress in stem cell research means we can now model human disease in a dish,” said Chandran, the team’s principle investigator, in a prepared statement. The program will address the fundamental question of whether astrocytes with gene mutations are helpful or harmful to motor neurons, potentially leading to new therapeutic targets.
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