RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease
| Autor: | Qin Li, Supriya Swarnkar, Marie-Laure Thiolat, Tommaso Nuzzo, George Tsaprailis, Gogce Crynen, Nicole Galli, Catherina Scharager-Tapia, Mehdi Eshraghi, Arianna De Rosa, Erwan Bezard, Neelam Shahani, Srinivasa Subramaniam, Uri Nimrod Ramírez-Jarquín, Alessandro Usiello, Oscar Rivera |
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| Přispěvatelé: | Eshraghi, M, Ramírez-Jarquín, 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. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
MAPK/ERK pathway
Dyskinesia Drug-Induced Parkinson's disease Striatum Pharmacology Levodopa 03 medical and health sciences 0302 clinical medicine medicine Animals Guanine Nucleotide Exchange Factors Humans PI3K/AKT/mTOR pathway Research Articles 030304 developmental biology Mammals 0303 health sciences Multidisciplinary biology Chemistry TOR Serine-Threonine Kinases SciAdv r-articles Parkinson Disease medicine.disease Abnormal involuntary movement Corpus Striatum nervous system diseases DNA-Binding Proteins Disease Models Animal Dyskinesia biology.protein Guanine nucleotide exchange factor medicine.symptom 030217 neurology & neurosurgery RHEB Research Article Neuroscience |
| Zdroj: | Science Advances |
| Popis: | A novel molecular target that signals abnormal involuntary movement in Parkinson’s disease treatment is discovered. 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. |
| Databáze: | OpenAIRE |
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