RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease

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

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbereaaz7001
JournalScience Advances
Volume6
Issue number18
DOIs
StatePublished - Apr 2020

ASJC Scopus subject areas

  • General

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