Scientists from the Gladstone Institutes have modified part of the huntingtin protein, protecting mice from the behavioral symptoms of Huntington’s disease, a hereditary neurodegenerative disease for which there is no cure.
Huntington’s is caused by a mutation in the Huntingtin gene, which codes for the protein of the same name. The condition triggers incorrect folding of the protein. Neurons cannot eliminate these misfolded proteins, so they accumulate in the brain, giving rise to symptoms including uncoordinated movement and loss of motor control, memory and learning problems and personality changes, such as dementia and aggression. Huntington’s is eventually fatal.
Gladstone’s Dr. Steve Finkbeiner and his team modified the huntingtin protein using phosphorylation; that is, they added a phosphate group to the molecule, according to a statement. Phosphorylation made the protein less toxic and easier for cells to remove, but modifying a specific point on the molecule called S421 prevented mouse models from developing Huntington’s symptoms altogether.
“I was shocked at the profound effect phosphorylation had on the Huntington’s model mice,” said first author Dr. Ian Kratter in the statement. “They showed few signs of the motor dysfunction, depression, or anxiety that are characteristic of the disease. In most of our tests, they were virtually indistinguishable from healthy mice.”
The team is now investigating ways to reproduce the effects of phosphorylation using a drug. They also hope that the findings will have applications beyond Huntington’s: “ [Much] of the work we’ve done points to these protein removal pathways as being important not only for Huntington’s disease, but also for other neurodegenerative disorders,” Finkbeiner said in the statement. “Understanding how phosphorylation links to these pathways could help treat several different brain diseases.”
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