Reversal of Neuropathology and Motor Dysfunction in a Conditional Model of Huntington's Disease

TLDR

Huntington’s disease is a neurodegenerative disorder marked by progressive, often irreversible clinical decline and neuronal protein aggregates. The study aims to use a conditional transgenic model to investigate how mutant huntingtin expression drives disease progression. A tet‑regulatable system was employed to generate a conditional HD mouse model. Mice expressing mutant huntingtin developed inclusions, neuropathology, and motor deficits, but silencing the transgene in symptomatic animals eliminated inclusions and restored behavior, indicating that ongoing mutant protein expression is required for pathology and that HD may be reversible.

Abstract

Neurodegenerative disorders like Huntington's disease (HD) are characterized by progressive and putative irreversible clinical and neuropathological symptoms, including neuronal protein aggregates. Conditional transgenic models of neurodegenerative diseases therefore could be a powerful means to explore the relationship between mutant protein expression and progression of the disease. We have created a conditional model of HD by using the tet-regulatable system. Mice expressing a mutated huntingtin fragment demonstrate neuronal inclusions, characteristic neuropathology, and progressive motor dysfunction. Blockade of expression in symptomatic mice leads to a disappearance 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 reversible.