PXD017434

PXD017434 is an original dataset announced via ProteomeXchange.

Title	RasGRP1 is a Causal Factor in the Development of L-DOPA-induced dyskinesia in Parkinson Disease
Description	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.
HostingRepository	PRIDE
AnnounceDate	2020-05-26
AnnouncementXML	Submission_2020-05-26_15:49:02.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	gogce crynen
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-02-07 07:39:54	ID requested
⏵ 1	2020-05-26 15:49:03	announced

Eshraghi M, Ram, í, rez-Jarqu, í, n UN, Shahani N, Nuzzo T, De Rosa A, Swarnkar S, Galli N, Rivera O, Tsaprailis G, Scharager-Tapia C, Crynen G, Li Q, Thiolat ML, Bezard E, Usiello A, Subramaniam S, RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease. Sci Adv, 6(18):eaaz7001(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: RasGRP1, dyskinesia, Parkinson Disease

Srinivasa Subramaniam
contact affiliation	Associate Professor, Neuroscience, The Scripps Research Institute Florida
contact email	SSubrama@scripps.edu
lab head
gogce crynen
contact affiliation	The scripps research institute
contact email	gcrynen@scripps.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017434
     1. Label: PRIDE project
     2. Name: RasGRP1 is a Causal Factor in the Development of L-DOPA-induced dyskinesia in Parkinson Disease