Neurodegenerative disease: preventing dyskinesia

L-DOPA is an effective treatment for Parkinson’s disease (PD), but long-term therapy is associated with a progressive loss of motor control. Using the well-established mouse model of PD, in which the nigrostriatal pathway is selectively damaged by the toxin 6-hydroxydopamine, Santini et al. show that dyskinesia may develop as repeated administration of L-DOPA promotes mammalian target of rapamycin (mTOR) signaling through dopamine D1 receptor-mediated activation of the mTOR complex 1 (mTORC1). Mice with induced PD activated mTORC1 and exhibited dyskinesia when treated with L-DOPA alone. Similar mice treated with L-DOPA and rapamycin, which inhibits mTOR, benefited from the therapeutic action of L-DOPA and remained free of motor side effects. This indicates that rapamycin and other drugs that target the mTORC1 signaling cascade may warrant further investigation for their potential as anti-PD therapies.