Research ArticleNeuroscience

Inhibition of mTOR Signaling in Parkinson’s Disease Prevents l-DOPA–Induced Dyskinesia

Science Signaling  21 Jul 2009:
Vol. 2, Issue 80, pp. ra36
DOI: 10.1126/scisignal.2000308

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Dyskinesia Relief

In its role as a regulator of cell growth, the mammalian complex of rapamycin (mTOR) phosphorylates several proteins involved in protein synthesis, such as 4E-BP (eukaryotic initiation factor 4E binding protein) and S6K (p70 S6 kinase), in response to growth factors and nutrient availability. Santini et al. show that l-DOPA, the most commonly used medication to alleviate the immobility and rigidity (akinesia) characteristic of Parkinson’s disease (PD), also stimulates the rapamycin-sensitive mTOR complex 1 (mTORC1). In a mouse model of PD, l-DOPA treatment increased phosphorylation of several direct and indirect mTOR targets, including S6K, its substrate ribosomal protein S6 (S6), 4E-BP, and eukaryotic initiation factor 4E (eIF4E). These phosphorylation increases required the activity of dopamine D1 receptors and extracellular signal–regulated kinase (ERK). Furthermore, increased phosphorylation of S6K, S6, 4E-BP, and eIF4E correlated with stronger abnormal involuntary movements (AIMs), a measure of dyskinesia (a side effect of l-DOPA that limits its clinical use). Administration of rapamycin, which predominantly inhibits mTORC1, decreased the severity of AIMs without affecting the ability of l-DOPA to reduce akinesia. Thus, the mTORC1 signaling pathway could be targeted in PD patients suffering from the dyskinesia associated with l-DOPA treatment.