Harmful proteins must be eliminated
Huntington's disease is a rare but severe genetic disorder caused by a mutation in the huntingtin gene. This change results in an altered variant of the huntingtin protein encoded by the gene. “It contains extended glutamine chains that cause the protein to misfold, rendering it unable to properly perform its function,” explains Nguyen. Misfolded proteins are dangerous to the body and must be broken down. However, the mutated huntingtin protein is not removed efficiently and instead accumulates. Patients with this disease eventually experience symptoms such as movement disorders, dementia, and psychiatric abnormalities. “There is still no cure for Huntington's disease. All patients die from it at some point,” says Nguyen.
Together with his team and international partners, the human geneticist is investigating the foundations of the disease and attempting to uncover its underlying mechanisms. In their current study, the researchers took a close look at the degradation of the proteins involved. “Before a damaged or misfolded protein can be broken down, it is tagged and transported to the cell's degradation complex,” Nguyen explains. “Ubiquitin tagging at two specific positions in the huntingtin protein, K6 and K9, plays a key role in the degradation and distribution of the protein in the cell.” Once tagged, the proteins are transported to the proteasome, the cell's central protein degradation system, and eliminated.
Blocking the tagging positions worsens the disease
The researchers were able to observe this process in cell culture during a previous study. Now they have replaced the mouse huntingtin gene with a disease-causing human variant in a special knock-in mouse model. In a different mouse line, the sites K6 and K9 in the huntingtin protein were altered to prevent ubiquitin tagging. “We observed that the symptoms of Huntington's disease worsened considerably,” reports Nguyen. “Signs of the disease also manifested earlier than in mice that only carried the huntingtin mutation.”
The researchers hope that this insight will provide a basis for future therapies. “Knowing the relevant tagging sites could make it possible to stimulate the degradation of damaged huntingtin protein,” says Nguyen. “We believe that the mutated protein escapes degradation because the disease-induced structural change and disrupted ubiquitin tagging at crucial sites inhibit its breakdown.”
Proceedings of the National Academy of Sciences
Experimental study
Animals
Prevention of Ubiquitination at K6 and K9 in Mutant Huntingtin Exacerbates Disease Pathology in a Knock-in Mouse Model
8-Jan-2026