Modulating proteolysis in Huntington disease: Eluding the toxic fragment

Huntington’s disease is an inherited neurodegenerative disorder primarily caused by the early death of brain cells. The disease typically begins with mental and emotional disturbances, which progress to involuntary, jerky movements. An abnormal form of the Huntingtin protein is associated with Huntington's disease. Huntingtin is made of 3144 amino acids, or molecular building blocks. In a landmark study, after mutating just one of those building blocks, genetically modified caspase-resistant mice (those resistant to intracellular proteins that lead to cell disintegration) were completely protected from all symptoms of Huntington’s disease. Jeffrey Carroll’s research aims to find medical interventions beyond genetic modification that produce the same effect. He is developing tools to quickly analyze the effectiveness of drugs at inhibiting cell disintegration. He has designed and is building a cell-based system that allows him to screen libraries of hundreds of thousands of drugs that might offer some protection. Carroll is also investigating a protein-cutting enzyme, caspase-2, who’s activity is dramatically reduced in caspase-resistant mice. Carroll aims to increase understanding of the pathway between Huntingtin and caspase-2. Findings could contribute to therapies for Huntington’s disease.