Huntington’s is an inherited disease that kills brain cells in the striatum – a small brain region that controls movement and also affects perception, thinking, awareness, judgement and behavior. The barrage of toxicity that causes the damage is selective – other parts of the brain remain relatively intact.
Some time ago, scientists established that Huntington’s disease arises from an inherited mutation in the protein “huntingtin.”
The faulty protein gathers in all cells of the body, but it only seems to affect a particular part of the brain.
This selective feature of the disease led a group of scientists at Johns Hopkins University in Baltimore, MD, to search for another culprit – they looked for proteins that interact with huntingtin only in the striatum.
In 2009, they reported that an activating protein called Rhes was a likely trigger for brain cell damage in Huntington’s disease.
The leader of that group was a postdoctoral fellow called Srinivasa Subramaniam, who is now an assistant neuroscience professor at The Scripps Research Institute (TSRI) in Jupiter, FL.
Now, in a new study published in the journal Neurobiology of Disease, Prof. Subramaniam and his team at TSRI establish conclusively that Rhes plays a pivotal role in focusing the toxicity of Huntington’s disease in the striatum.
In the earlier study, the researchers showed that Rhes binds to a series of repeats in huntingtin. It is this that causes the death of brain cells.
In the new study, Prof. Subramaniam and colleagues show that deleting Rhes significantly reduces behavioral problems in mouse models of Huntington’s disease.
They also took the earlier findings further and showed that adding Rhes to the cerebellum – a brain region normally not affected in Huntington’s – caused the animals to experience loss of motor functions such as balance and coordination.
In addition, they found the animals’ cerebellum contained lesions and damaged neurons – confirming that Rhes triggers toxicity and that even regions normally not damaged in Huntington’s disease can become vulnerable if the activating protein is overexpressed.
Prof. Subramaniam says the biggest result to emerge from the study is that Rhes is likely a good drug target for Huntington’s disease, and adds:
“Drugs that disrupt Rhes could alleviate Huntington’s pathology and motor symptoms.”
“We think, by targeting Rhes, we might block the initiation of Huntington’s, which we predict would afford protection against psychiatric-related problems as well.”
The State of Florida helped to sponsor the study.
In October 2014, Medical News Today reported another study by Prof. Subramaniam and his team that showed how a relationship between huntingtin and the gene mTORC1 can trigger onset of Huntington’s disease and lead to exacerbation of symptoms.