Cause of damage from Huntington's disease 'discovered'

Huntington's disease is a genetic disease with no cure, characterised by a steady decline in motor control and the dysfunction and death of brain cells. The cause of the disease has long baffled doctors.

Now, an international team led by Melbourne University in Australia, has identified the behaviour of mutant protein "huntingtin" which actually leads to the Huntington's disease, the 'Journal of Biological Chemistry' reported.

In fact, the new research has shown that the build-up of damaging proteins causes steady damage, rather than slowly building up to a toxic level.

Using state of the art technology, the scientists observed how the human mutant "huntingtin" proteins form into large clumps, which kills brain cells and leads to progressed Huntington's disease.

"Steps prior to the clustering of the mutated proteins were thought to damage cells, but these steps were not clearly detectable under a microscope.

"Understanding this process and finding the right target to block the ultimate death of the brain cells has been extremely difficult to determine," Dr Danny Hatters, who led the team, said.

The technology called analytical ultracentrifugation and the methodology the scientists developed enabled them to visualise this process in much greater detail.

"What we have shown and are the first to show, is that mutated huntingtin protein forms three different sized clusters in the damaged cells. The discovery will help develop a targeted treatment that shuts down the key processes causing clusters to form and for the disease to progress," he said.

While doctors previously thought that small clusters of the mutant protein kept accumulating over time until they overwhelmed and killed the brain cells, Dr Hatters' team found that these clusters were static, which means they form in a more unpredictable manner than previously thought.

The discovery reveals the clusters place a steady stress on cells over time rather than steadily building up over time to some critical "toxic" level.

"Why it takes so long for the cells to die in human disease is not known -- however it could be that cells eventually cannot compensate anymore from the process where toxicity is built up to form one cluster called oligomers.

"The real key of our work is that we now have direct targets in the critical steps in the process of cell toxicity and death and to gauge any therapeutic effects of drugs on these targets. We can also measure how this alleviates cellular toxicity and brain cell death," he said.

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