Researchers Reverse Huntington’s Defects in Cell Model

Using a new Huntington’s disease model featuring two types of disease affected neurons grown together in the lab, researchers showed that introducing a specific protein part reduced mutant huntingtin, as well as other molecular effects linked to the disease.

Findings presented in the study titled “TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease,” published in the journal Proceedings of the National Academy of Sciences (PNAS), open up research to further explore if the protein, called TRiC, could be used in developing new treatments for Huntington’s disease.

The new disease model recreated the changes observed in the brains of Huntington’s patients. A network of nerve cells, known as the corticostriatal pathway, connects two parts of the brain, which are both affected in Huntington’s; the outermost layer called the cortex, and a deep structure known as the striatum.

Researchers at the University of California, San Diego (UCSD) grew cortex neurons, isolated from mice carrying the human mutated huntingtin gene, side by side with nerve cells from the striatum. The cells were cultured in a specialized dish, allowing cortical neurons to connect to the striatal ones.

Researchers noted that the cells developed several of the features characteristic of Huntington’s. They could not properly transport BDNF (brain-derived neurotrophic factor), a growth factor healthy neurons need, and the neurons were connected in far fewer spots than those isolated from healthy mice. Defects in cortical neurons also made striatal neurons die, just as suspected in the case of patients.

Earlier studies have suggested that parts of the TRiC protein can reduce the levels of mutant huntingtin. When researchers added such a protein part to the cell culture, they observed that not only was there less mutant huntingtin in the cells, the protein also improved BDNF transport and prevented the death of striatal neurons.

“Our experimental design provides an invaluable system for studying important cellular and molecular events underlying Huntington’s disease,” first author Xiaobei Zhao, PhD, a postdoctoral scientist in the Department of Neurosciences at UCSD, said in a news release.

“The next step is to test this in vivo. If the phenotype of the Huntington’s disease mouse model can be rescued, it’s possible that TRiC could be used to treat Huntington’s disease,” added Zhao.