| First Author | Eshraghi M | Year | 2020 |
| Journal | Sci Adv | Volume | 6 |
| Issue | 18 | Pages | eaaz7001 |
| PubMed ID | 32426479 | Mgi Jnum | J:299349 |
| Mgi Id | MGI:6492017 | Doi | 10.1126/sciadv.aaz7001 |
| Citation | Eshraghi M, et al. (2020) RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease. Sci Adv 6(18):eaaz7001 |
| abstractText | 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. |
