A new study reveals one way to stop proteins from triggering an energy failure inside nerve cells during Huntington’s disease, an inherited genetic disorder caused by mutations in the gene that encodes huntingtin protein.
Researchers have been looking for proteins that interact with mutant huntingtin to better understand the initial steps of Huntington’s disease progression.
In the study, published in Nature Communications, researchers characterized one protein, valosin-containing protein (VCP) that the research team found in high abundance inside nerve cell mitochondria. The scientists discovered that VCP is recruited to nerve cell mitochondria by mutant huntingtin protein. Nerve cells with VCP-mutant huntingtin interacting inside them became dysfunctional and self-destructed.
The researchers worked to identify ways to prevent VCP from heading to nerve cell mitochondria and interacting with mutant huntingtin protein once inside. The team identified the regions of VCP and mutant huntingtin that were interacting. They designed a small protein, or peptide, with the same regions to disrupt the VCP-mutant huntingtin protein interaction. In nerve cells exposed to their peptide, VCP and mutant huntingtin bound the peptide instead of each other. Nerve cells exposed to the novel peptide had healthier mitochondria than unexposed cells. In fact, the peptide prevented VCP from relocating to mitochondria at all, and prevented nerve cell death.
To determine if the peptide had more than subcellular effects, and if it could be used therapeutically to prevent Huntington’s disease symptoms, the researchers administered the peptide to mice with Huntington’s-like disease and assessed mouse motor skills. Huntington’s-like mice exhibit spontaneous movement including excessive clasping, poor coordination, and decreased lifespan. Mice treated with the novel peptide did not experience these symptoms and appeared healthy. They concluded that the peptide reduced nerve cell impairment caused by Huntington’s disease in the animal model.
The next step for the researchers will be to optimize the potentially therapeutic peptide for use in human studies.
Reprinted from materials provided by Case Western Reserve University.