Kimby N. Barton, MSc
Geriatrics & Aging
Dramatic results presented in Cell have demonstrated that turning off the expression of a mutated protein in mice with Huntington's disease, results in either a cessation or a reversion of the symptoms associated with the disease.
Huntington's disease (HD) is an autosomal dominant inherited disorder characterized by motor disturbances such as chorea and dystonia, personality changes, and cognitive decline. These symptoms seem to result from neural degeneration, which occurs primarily in the striatum and cortex of the brain. HD typically manifests in mid-life and death follows 10 to 20 years after disease onset. Currently, no specific cure or treatment is available.
HD is caused by an expansion of glutamine (CAG) repeats near the 5' end of the gene that codes for a protein called huntingtin. The translated protein then contains an expanded glutamine (polyQ) sequence in the N-terminal portion. Normal individuals possess a polyQ length of approximately 6 to 34 repeats whereas individuals with more than 40 repeats develop HD. The longer the polyQ expansion, the earlier the onset of symptoms.
The pathogenesis of HD is poorly understood. It is believed that somehow the expansion of the polyQ sequence in the N-terminal portion of the protein results in a deleterious gain of function mechanism. Neuronal nuclear aggregates are found in the brains of patients with the disease as well as in transgenic animal models studied to date. These aggregates contain the mutant huntingtin protein and are also often found to be ubiquitinated suggesting that they have been targeted for proteasomal degradation. However, it remains to be determined whether these nuclear aggregates are themselves responsible for the neural degeneration or whether they are merely a byproduct of some other toxic response.
Amazingly, suppression of the mutant protein in mice between the ages of 18 and 34 weeks either halted or reversed the different aspects of the HD-like phenotype.
In this study, researchers created a conditional model of HD by expressing a mutated huntingtin protein under the control of a tet-regulated system. Essentially, they expressed a mutant protein in mice and looked at the effect it had on neuropathology of the brain and on the behaviour of the mice. Mice with the mutated huntingtin protein 'turned on' developed neuronal nuclear aggregates and showed behaviour consistent with that of having HD. Mice, as young as 4 weeks of age, were beginning to exhibit unusual behaviour. By 20 weeks, some, but not all, of the mice began to show a mild tremor that developed into a jerking motion. By 36 weeks the HD mice were clearly hypoactive and remained so until their death.
The most interesting part of the study, was when the researchers were able to turn the mutant protein 'off'. Adding an antibiotic to water consumed by the mice, turned off gene expression of the mutated protein. Amazingly, suppression of the mutant protein in mice between the ages of 18 and 34 weeks either halted or reversed the different aspects of the HD-like phenotype. Specifically, the neuronal and nuclear aggregates in the brain disappeared, the number of reactive astrocytes decreased, and the progressive striatal atrophy along with the decrease in D1 receptor levels was halted. In addition, stopping the expression of the HD gene prevented the further exacerbation of the HD behavioural characteristics and ameliorated their condition to a degree approaching those in control mice.
This is the first study that has ever demonstrated that the symptoms and characteristics of HD are reversible, implying that irreversible changes which commit the cell to neuronal dysfunction or death have not necessarily taken place. The findings also suggest that therapeutic approaches to target and specifically destroy the mutant huntingtin protein may be effective in returning patients with HD to a normal phenotype. Understanding the mechanisms responsible for this disease may provide new targets for therapeutic interventions in patients suffering from HD and other progressive neurodegenerative disorders.
- Yamamoto A., Lucas JJ. and Hen R. 2000. Cell. 101:57-66.