Science Advances
American Association for the Advancement of Science

The therapeutic effects of l-3,4-dihydroxyphenylalanine (l-DOPA) in patients with Parkinson’s disease (PD) severely diminishes with the onset of abnormal involuntary movement, l-DOPA–induced dyskinesia (LID). However, the molecular mechanisms that promote LID remain unclear. Here, we demonstrated that RasGRP1 [(guanine nucleotide exchange factor (GEF)] controls the development of LID. l-DOPA treatment rapidly up-regulated RasGRP1 in the striatum of mouse and macaque model of PD. The lack of RasGRP1 in mice (RasGRP1−/−) dramatically diminished LID without interfering with the therapeutic effects of l-DOPA. Besides acting as a GEF for Ras homolog enriched in the brain (Rheb), the activator of the mammalian target of rapamycin kinase (mTOR), RasGRP1 promotes l-DOPA–induced extracellular signal-regulated kinase (ERK) and the mTOR signaling in the striatum. High-resolution tandem mass spectrometry analysis revealed multiple RasGRP1 downstream targets linked to LID vulnerability. Collectively, the study demonstrated that RasGRP1 is a critical striatal regulator of LID. is a causal factor in the development of <span style="font-variant: all-small-caps">l</span>-DOPA–induced dyskinesia in Parkinson’s disease&author=Mehdi Eshraghi,Uri Nimrod Ramírez-Jarquín,Neelam Shahani,Tommaso Nuzzo,Arianna De Rosa,Supriya Swarnkar,Nicole Galli,Oscar Rivera,George Tsaprailis,Catherina Scharager-Tapia,Gogce Crynen,Qin Li,Marie-Laure Thiolat,Erwan Bezard,Alessandro Usiello,Srinivasa Subramaniam,&keyword=&subject=Research Article,Research Articles,SciAdv r-articles,Neuroscience,Neuroscience,