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 - 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.
UR - https://www.scopus.com/pages/publications/85084638127
UR - https://www.scopus.com/pages/publications/85084638127#tab=citedBy
U2 - 10.1126/sciadv.aaz7001
DO - 10.1126/sciadv.aaz7001
M3 - Article
C2 - 32426479
AN - SCOPUS:85084638127
SN - 2375-2548
VL - 6
JO - Science Advances
JF - Science Advances
IS - 18
M1 - eaaz7001
ER -