Neurodegeneration: Clearing mutant protein associated with Huntington’s disease

A study identifying compounds that can reduce levels of the mutant protein implicated in Huntington’s disease is published in Nature this week. This is a proof-of-principle study, and more work is needed before this approach can be applied in the clinic.

Huntington's disease is currently incurable. It is caused by a mutation in the gene encoding the Huntingtin protein, which leads to an accumulation of the mutant protein in neurons, eventually causing them to die. Lowering levels of the disease-causing protein is an attractive treatment strategy, but it needs to be specific, as the healthy (wild-type) version of the protein has important functions in the brain.

Boxun Lu and colleagues propose a new approach to clearing mutant Huntingtin - identifying small molecules that bind to both the mutant protein (but not the wild type) and a key component of the cell’s autophagic protein-degradation machinery. They show that these compounds reduce levels of mutant Huntingtin in cultured mouse and human nerve cells, and in mouse and fly models of Huntington's disease, whereas levels of normal Huntingtin remain unchanged. The treatment reduced neurodegeneration in the cells and improved motor function in the animal models.

The authors propose that, should this treatment prove successful for Huntington’s disease, the strategy could potentially be extended to other diseases involving accumulation of mutant proteins. In an accompanying News & Views, Huda Zoghbi notes that “long-term preclinical trials in mice will be necessary to ascertain that the benefit is sustained and robust over the course of chronic therapy”.