The genetic defect behind Huntingtonās disease causes malfunctions in mitochondria, the energy-producing components of cells, new work shows. The finding should help explain how the mutation causes the disease and could lead to new approaches to treatment.
Since 1993, researchers have known that Huntingtonās ā an incurable and fatal brain disorder ā is caused by a defect in a single gene that encodes a protein called huntingtin.
They have also long suspected that some of the symptoms of the disorder are due to defects in mitochondria. Now, for the first time, a team led by Alexander Panov at Emory University, US, have directly linked the two.
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Panovās work suggests that huntingtin kills brain cells, at least in part, by causing mitochondria in the cells to respond abnormally to a type of chemical stress. This causes the mitochondria to spill some of their contents. And this could cause cell death, Panov thinks.
āThis study brings together several lines of research,ā says Elena Cattaneo, a pharmacologist at the University of Milan. āIt shows how the mitochondria are linked to the toxicity of the mutant gene.ā
New drugs
Panovās team examined mitochondria from blood cells of patients with Huntingtonās disease and from brain cells of engineered mice that produce mutant huntingtin. They found that these mitochondria could not handle a certain kind of stress caused by calcium as well as normal mitochondria.
The researchers also found that mutant huntingtin can bind directly to normal mitochondria and cause them to respond abnormally to calcium-induced stress. This āstressā happens during part of the normal signalling process in the brain.
Cattaneo believes the finding could lead to new drugs that would alleviate some of the symptoms of the disorder by correcting the defective mitochondria. āThis may really open up some new perspectives for treating Huntingtonās disease,ā she says.
But M. Flint Beal, a neuroscientist at Cornell University, believes that more experiments must be done to determine whether the mitochondrial defect that Panov has observed really causes Huntingtonās disease.
Other factors
āIām not entirely sure that this is the whole story in the living person,ā he argues. āThey havenāt proven that this [mitochondrial defect] causes what happens in patients.ā
Panov agrees that mutant huntingtin might cause cell death and disease by affecting other factors besides the mitochondria.
āWhat Iāve discovered is one mechanism,ā he admits. āBut itās probably not the only one.ā
Huntingtonās disease affects one in 10,000 people. A child of a sufferer has a 50 per cent chance of developing the disease. Journal reference: Nature Neuroscience (DOI: 10.1038/nn884)
