Striatal ΔFosB gene suppression inhibits the development of abnormal involuntary movements induced by L-Dopa in rats.

Abstract

L-Dopa-induced dyskinesia (LID) is associated with upregulation of striatal ΔFosB in animal models and patients with Parkinson’s disease (PD). A mechanistic role of ΔFosB is suspected because its transgenic overexpression leads to early appearance of LID in rodents and primates. The present study in rodents is aimed at exploring the therapeutic potential of striatal ΔFosB gene suppression to control LID in patients with PD. To determine the effect of reducing striatal ΔFosB expression, we used RNAi gene knockdown in a rat model of PD and assessed abnormal involuntary movements (AIMs) in response to L-Dopa. Rats with dopamine depletion received striatal injections of rAAV-ΔFosB shRNA or a control virus before exposure to chronic L-Dopa treatment. Development of AIMs during the entire L-Dopa treatment period was markedly inhibited by ΔFosB gene knockdown and its associated molecular changes. The antiparkinsonian action of L-Dopa was unchanged by ΔFosB gene knockdown. These results suggest a major role for ΔFosB in the development of LID, and support exploring strategies to reduce striatal ΔFosB levels in patients with PD.