Dataset Information

RasGRP1 is a Causal Factor in the Development of L-DOPA-induced dyskinesia in Parkinson Disease

ABSTRACT: The therapeutic benefits of L–3,4–dihydroxyphenylalanine (L-DOPA) in Parkinson’s disease (PD) patients severely diminishes with the onset of L-DOPA-induced dyskinesia (LID), a debilitating motor side effect. LID is mainly due to altered dopaminergic signaling in the striatum, a brain region that controls motor and cognitive functions. However, the molecular mechanisms that promote LID remain unclear. Here, we have reported that increased striatal RasGRP1 (also known as CalDAG-GEF-II) is instrumentally linked to the development of LID in a 6-hydroxydopamine (6-OHDA) lesioned mouse model of PD. L-DOPA treatment rapidly upregulated RasGRP1 in the dopamine-1 receptor positive neurons in the dorsal striatum. RasGRP1 deleted mice (RasGRP1–/–) had drastically diminished LID, and RasGRP1–/– mice did not interfere with the therapeutic benefits of L-DOPA. In terms of its mechanism, RasGRP1 mediated L-DOPA-induced extracellular regulated kinase (ERK), the mammalian target of rapamycin kinase (mTOR) and the cAMP/PKA pathway. RasGRP1 bind directly with and acts 2 as a guanine nucleotide exchange (GEF) for Ras-homolog-enriched in the brain (Rheb), a potent activator of mTOR, both in vitro and in the intact striatum. High-resolution tandem mass tag mass spectrometry analysis of striatal tissue revealed significant targets, such as phosphodiesterase 10a (Pde10a), Pde2a, catechol-o-methyltransferase (Comt), and glutamate decarboxylase 1 and 2 (Gad1 and Gad2), as downstream regulators of RasGRP1 that are linked to LID vulnerability. Moreover, we found that RASGRP1 protein is also upregulated predominantly in the striatum of MPTP-lesioned macaque treated with L-DOPA, emphasizing the translational potential of this protein. Collectively, the findings of this study demonstrated that RasGRP1 is a major regulator of LID in the dorsal striatum. Pharmacological or gene-depletion strategies targeting RasGRP1 may offer novel therapeutic opportunities for preventing LID in PD patients.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: gogce crynen

LAB HEAD: Srinivasa Subramaniam

PROVIDER: PXD017434 | Pride | 2020-05-22

REPOSITORIES: Pride

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			Action	DRS
	MS219033_NS_SS_PLEX1_3_NonPHOSPHO.mzTab	Mztab
	MS219033_NS_SS_PLEX1_3_PHOSPHO.mzTab	Mztab
	MS219033_NS_SS_PLEX1_NonPHOSPHO.msf	Msf
	MS219033_NS_SS_PLEX1_NonPHOSPHO.raw	Raw
	MS219033_NS_SS_PLEX1_PHOSPHO.msf	Msf

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

Eshraghi Mehdi M Ramírez-Jarquín Uri Nimrod UN Shahani Neelam N Nuzzo Tommaso T De Rosa Arianna A Swarnkar Supriya S Galli Nicole N Rivera Oscar O Tsaprailis George G Scharager-Tapia Catherina C Crynen Gogce G Li Qin Q Thiolat Marie-Laure ML Bezard Erwan E Usiello Alessandro A Subramaniam Srinivasa S

Science advances 20200501 18

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 RasG ...[more]

PMID: 32426479

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