Clumps of defective proteins, long implicated in killing off part of the brain in Huntington’s disease, may actually be helping these neurons to survive. The discovery could redirect efforts to develop treatments for Huntington’s disease (HD) – a disorder that slowly kills brain cells involved in movement and higher cognitive function.
HD is triggered by mutations in a protein called huntingtin which cause the protein to aggregate and ultimately form large cellular blobs known as inclusion bodies. These insoluble blobs are visible under a microscope and may contain thousands of mutant proteins. Scientists had believed that inclusion bodies help destroy neurons, since animals sick with HD have these blobs in their brain cells while healthy animals do not. And, in general, the sicker animals become with the disease, the more inclusion bodies are found in the neurons of damaged brain areas.
True culprits
"This is a seminal paper," says Harr Orr who studies brain diseases at the University of Minnesota in Minneapolis. "It compromises one of the major theories of how huntingtin causes disease." Orr says the work also suggests that the smaller, soluble groups of huntingtin - that ultimately create the large inclusions - may be the true culprits behind the disease.
Until now, it had not been possible to follow the effects of inclusions on individual neurons, so it was not clear if they were in fact responsible for neuron death, says Steve Finkbeiner of the University of California, San Francisco, US, who led the study.
For example, the inclusion bodies may have been a by-product of the true pathogenic process, and actually harmless themselves. Or, even more intriguing, the blobs could actually have been a protective mechanism by which cells fought to limit the damage done by the mutant protein. "The possibilities kept me up at night," says Finkbeiner. "The more I thought about it, the more I realised we needed a new way to address this problem."
Clear-cut results
So his team developed a way to track the life, death and history of inclusion body formation in a large number of individual rat neurons, grown in dishes. The rat cells were genetically engineered to produce mutant huntingtin proteins, and each neuron was scanned regularly by an automated microscope.
The results were clear-cut: increased levels of the mutant protein meant a cell was more likely to die but the appearance of inclusion bodies predicted the cells would actually survive for longer than their peers. While Finkbeiner admits it is possible that neurons in the brain respond differently to inclusion bodies than neurons in a dish, the rat neuron model has already proven to faithfully mimic more than a dozen different cellular aspects of HD.
He also points out that the aggregation of huntingtin might still play a detrimental role in the disease. But the extremely large protein clumps that form inclusion blobs appear to be a sign of cells fighting back, he says. The result could change the development of HD therapy. Researchers are already looking for drugs that keep huntingtin from aggregating. But some of these drugs might prevent the formation of protective inclusion bodies while allowing the smaller – and possibly lethal - groups of huntingtin to form. "One prediction of ours is that some of these drugs could actually make the disease worse," he says.
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Journal reference: Nature (vol 431, p 805)
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Created: Mar. 6, 2005
Last updated: Dec. 5, 2010