Reversal of neuropathology and motor dysfunction in a conditional model ofHuntington's disease

Neurodegenerative disorders like Huntington's disease (HD) are characterize d by progressive and putative irreversible clinical and neuropathological s ymptoms, including neuronal protein aggregates. Conditional transgenic mode ls of neurodegenerative diseases therefore could be a powerful means to exp lore the relationship between mutant protein expression and progression of the disease. We have created a conditional model of HD by using the tet-reg ulatable system. Mice expressing a mutated huntingtin fragment demonstrate neuronal inclusions, characteristic neuropathology, and progressive motor d ysfunction. Blockade of expression in symptomatic mice leads to a disappear ance of inclusions and an amelioration of the behavioral phenotype. We thus demonstrate that a continuous influx of the mutant protein is required to maintain inclusions and symptoms, raising the possibility that HD may be re versible.