When expression of a transgene encoding the protein responsible for Huntington's disease was turned off in a mouse model, the animals failed to develop the characteristic neuropathology or progressive motor dysfunction of the disease.

The authors of the study conclude in the March 31st issue of Cell that "a continuous influx of the mutant protein" is necessary for maintenance of symptoms, suggesting that Huntington's disease may be reversible.

Dr. Rene Hen and colleagues of Columbia University in New York, New York, created a conditional transgenic mouse model of Huntington's disease by using the tetracycline-responsive gene system, which enables expression of a transgene to be turned off with tetracycline analogs. The mice carried both a chimeric mouse/human exon 1 of the huntingtin gene with a polyQ expansion and beta-galactosidase (lacZ) reporter sequences.

The mice exhibited the mutated huntingtin fragment as well as other hallmarks of Huntington's disease, including neuronal inclusions, characteristic neuropathology and progressive motor dysfunction, Dr. Hen
and colleagues report.

To turn off expression of the polyQ-huntingtin transgene, the investigators treated mice with 2 mg/mL of doxycycline for 16 weeks. The doxycycline completely inhibited expression of the transgene as evidenced by lacZ staining.

Less than 1% of striatal neurons from treated mice stained positive for nuclear huntingtin at 34 weeks compared with 60% in untreated mice. Intra- and extranuclear aggregates also disappeared in the doxycycline group.

Dr. Hen's group observed "a clear arrest of neuropathology in the gene-off mice," and a halt to the progressive loss of D1 receptors that was seen in the untreated or gene-on mice. The doxycycline group also exhibited a reversal of the motor dysfunction to levels, in some cases, that were comparable to healthy, control mice.

"Turning off the expression of polyQ-huntingtin...results in either a halt or a reversion of the different phenotypes," Dr. Hen and colleagues say. "This implies that irreversible changes that commit the cell to neuronal dysfunction or death have not necessarily taken place."

The authors add that "therapeutic approaches aimed either to destroy or inactivate the mutant huntingtin protein might be effective." They further note that "the elucidation of the mechanisms responsible may provide new targets for therapeutic interventions for patients suffering from Huntington's disease and other neurodegenerative disorders."

SOURCE - Cell 2000