Failure of cannibalization in Huntington disease

The inability to get rid of mutant protein accumulation in Huntington's disease (HD) is because the neuronal protein degradation machinery fails to recognize and package proteins for destruction. The work published online this week in Nature Neuroscience suggests potential therapeutic targets that may be beneficial for HD.

One of the cellular hallmarks of HD is the accumulation of the mutant protein Huntingtin which eventually leads to cell death in the brain. Normally, excess protein accumulation can be removed by a cellular process called autophagy in which cells digest their own components along with any proteins that are tagged for degradation. Abnormal autophagy is also seen in other neurodegenerative disorders.

Using cells collected from HD patients and mouse models of HD, Ana Maria Cuervo and colleagues show that the cellular 'vehicles' which deliver proteins to the degradation machinery, fail to recognize their cargoes. Because mutant Huntingtin is not cleared away properly, the scientists attribute this cellular defect to an increase of protein aggregates that is characteristic of HD cells.