TY - JOUR
T1 - RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease
AU - Eshraghi, Mehdi
AU - Ramírez-Jarquín, Uri Nimrod
AU - Shahani, Neelam
AU - Nuzzo, Tommaso
AU - de Rosa, Arianna
AU - Swarnkar, Supriya
AU - Galli, Nicole
AU - Rivera, Oscar
AU - Tsaprailis, George
AU - Scharager-Tapia, Catherina
AU - Crynen, Gogce
AU - Li, Qin
AU - Thiolat, Marie Laure
AU - Bezard, Erwan
AU - Usiello, Alessandro
AU - Subramaniam, Srinivasa
N1 - Funding Information: We would like to thank M. Carta, M. Morelli, M.E. De Stefano, and F. Errico for the critical reading of the manuscript. We would like to thank M. Benilous for administrative help, and members of the labs Subramanian and Usiello for continuous support and collaborative atmosphere. We like to thank the members at the Scripps animal facility, behavior core, and proteomics core for the help and expertise. T.N., A.D.R., and A.U. were supported by a grant from Fondazione Cariplo and Ricerca Ateneo, Università Campania (L. Vanvitelli). This research was supported by grant awards from NIH/NINDS R01-NS087019-01A1 and NIH/NINDS R01-NS094577-01A1 and partly from the Cure for Huntington Disease Initiative (CHDI) Foundation to S.Su. Publisher Copyright: © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.aaz7001
DO - 10.1126/sciadv.aaz7001
M3 - Article
C2 - 32426479
SN - 2375-2548
VL - 6
JO - Science Advances
JF - Science Advances
IS - 18
M1 - eaaz7001
ER -