Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract

Huntington’s disease is a neurodegenerative disorder in which misshapen proteins accumulate in the brain and kill neurons. The misshapen proteins form as a result of specific mutations in the gene that encodes a protein called huntingtin. These mutations result in a region of the protein called the polyQ tract being longer than normal. Other regions of huntingtin that are near to the polyQ tract can dramatically change the behavior of the mutant protein. Shen et al. investigated how these regions control the shape of mutant huntingtin and how this affects the toxicity of the mutant protein in neurons. The experiments found that the two regions on either side of the polyQ tract dramatically change the shape of mutant huntingtin proteins. In the absence of these flanking regions, the extended polyQ region is not very toxic, demonstrating that the flanking sequences play important roles in generating the toxic protein shapes. These flanking regions help mutant huntingtin to form a particular shape that was strongly linked with the death of neurons in rat brain slices. The flanking regions also change the way that the cellular machinery in neurons recognizes mutated huntingtin proteins and acts to prevent them from causing harm. Misshapen forms of other proteins are responsible for causing other neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Therefore, the findings of Shen et al. may help researchers to develop new drugs for these conditions, as well as for Huntingdon’s disease.