RasGRP1 (CalDAG-GEF-II) Mediates L-DOPA-induced Dyskinesia in a Mouse Model of Parkinson Disease

Ishragi, M.; Ramirez Jarquin, U. N.; Shahani, N.; Swarnkar, S.; Galli, N.; Rivera, O.; Tsaprailis, G.; Scharager-Tapia, C.; Crynen, G.; Usiello, A.; Subramaniam, S.

doi:10.1101/739631

bioRxiv · 10.1101/739631

RasGRP1 (CalDAG-GEF-II) Mediates L-DOPA-induced Dyskinesia in a Mouse Model of Parkinson Disease

Ishragi, M.·Ramirez Jarquin, U. N.·Shahani, N.·Swarnkar, S.·Galli, N.·Rivera, O.·Tsaprailis, G.·Scharager-Tapia, C.·Crynen, G.·Usiello, A.·Subramaniam, S.

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Abstract

The therapeutic benefits of L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson disease (PD) patients diminishes with the onset of abnormal involuntary movements (L-DOPA induced dyskinesia), a debilitating motor side effect. L-DOPA induced dyskinesia are due to altered dopaminergic signaling in the striatum, a brain region that controls motor and cognitive functions. However, the molecular mechanisms that promote L-DOPA-induced dyskinesia remain unclear. Here, we have reported that RasGRP1 (also known as CalDAG-GEF-II) physiologically mediated L-DOPA induced dyskinesia in a 6-hydroxy dopamine (6-OHDA) lesioned mouse model of PD. In this study, L-DOPA treatment rapidly upregulated RasGRP1 in the striatum. Our findings showed that RasGRP1 deleted mice (RasGRP1-/-) had drastically diminished L-DOPA-induced dyskinesia, and RasGRP1-/- mice did not interfere with the therapeutic benefits of L-DOPA. In terms of its mechanism, RasGRP1 mediates L-DOPA-induced extracellular regulated kinase (ERK), the mammalian target of rapamycin kinase (mTOR) and the cAMP/PKA pathway and binds directly with Ras-homolog-enriched in the brain (Rheb), which is 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 (Pde1c), Pde2a, catechol-o-methyltransferase (comt), and glutamate decarboxylase 1 and 2 (Gad1 and Gad2), which are downstream regulators of RasGRP1 and are linked to L-DOPA-induced dyskinesia vulnerability. Collectively, the findings of this study demonstrated that RasGRP1 is a major regulator of L-DOPA-induced dyskinesia in the striatum. Drugs or gene-depletion strategies targeting RasGRP1 may offer novel therapeutic opportunities for preventing L-DOPA-induced dyskinesia in PD patients.

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Ishragi, M., Ramirez Jarquin, U. N., Shahani, N., Swarnkar, S., Galli, N., Rivera, O., Tsaprailis, G., Scharager-Tapia, C., Crynen, G., Usiello, A., Subramaniam, S.. 2019-08-27. RasGRP1 (CalDAG-GEF-II) Mediates L-DOPA-induced Dyskinesia in a Mouse Model of Parkinson Disease. https://doi.org/10.1101/739631

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