A group of researchers from Case Western Reserve University School of Medicine believe that they’ve found a way to prevent a rogue protein from initiating energy failure inside the nerve cells of people who have Huntington’s disease.
An inherited genetic disorder, Huntington’s is caused when the gene that encodes huntingtin protein becomes mutated. This in turn has a detrimental effect on the mitochondria, the part of nerve cells that produce energy. The affected person gradually loses their ability to walk, talk and control their behaviour.
In order to gain a better understanding of the how Huntington’s disease develops, the researchers looked at the proteins that are known to interact with a mutant version of huntingtin, to see what effect it has on the mitochondria. They found that there was an abundance of a protein known as VCP inside the nerve cell mitochondria, which they believed was responsible for the damage to the cells.
By examining mice with mutant huntingtin they observed that their mitochondria were full of VCP. This concentration was also seen in donated nerve cells from people with Huntington’s disease. The team also observed that the VCP only interacted with the mutant protein, and there was no interaction between VCP and healthy huntingtin protein. This resulted in the nerve cells with the VCP-mutant huntingtin interaction becoming dysfunctional and ultimately self-destructing.
The researchers then looked at ways to stop VCP from binding with the nerve cell mitochondria and interacting with the mutant protein. By identifying the exact regions where this interaction took place, they were able to introduce a specially designed peptide that would disrupt this interaction. Following the introduction of this novel peptide, rather than binding together, the VCP and mutant mitochondria bound with the peptide instead. This meant that the nerve cells which had been exposed to this peptide retained healthy mitochondria and so prevented the death of the nerve cells.
The team then wanted to see what effect this peptide would have on typical Huntington’s symptoms. By administering it to mouse models of Huntington’s disease they found that the mice no longer exhibited typical symptoms such as poor coordination, spontaneous movement and decreased lifespan.
The team now hope to further investigate the potential for using this peptide to develop therapeutic treatments which can then be tested in human studies.
The research was published in Nature Communications.