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Targeting beta‐arrestins in the treatment of Parkinson's disease (796.6)
Author(s) -
Urs Nikhil,
Bezard Erwan,
Caron Marc
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.796.6
Subject(s) - dopamine , neuroscience , g protein coupled receptor , postsynaptic potential , striatum , parkinson's disease , dyskinesia , neurotransmitter , biology , receptor , dopamine receptor , signal transduction , pharmacology , microbiology and biotechnology , medicine , disease , central nervous system
Parkinson’s disease (PD) is a neurodegenerative disorder caused by the progressive loss of dopamine input to the striatum. Dopamine (DA) is a catecholamine neurotransmitter that is released by midbrain DA neurons and activates G‐protein coupled receptors (GPCRs) on postsynaptic striatal neurons. DA GPCRs are known to signal via both G‐protein‐ and beta‐arrestin2 (βarr2) dependent mechanisms and both pathways either individually or in combination, play a major role in control of movement. PD is characterized by severe locomotor deficits and is commonly treated with L‐DOPA, but its prolonged usage causes dyskinesias referred to as L‐DOPA induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias might be associated with G‐protein mediated signaling through DA receptors. Therefore, preventing G‐protein signaling in PD therapy may be an ideal way to eliminate associated dyskinesias. β‐arrestins have the unique ability to desensitize G protein signaling and at the same time independently activate signaling, thereby mediating locomotion. Our objective is to test the effect of over‐expression or deletion of βarr2 on L‐DOPA induced locomotion and dyskinesia potential in a rodent and non‐human primate PD model. Our results in the rodent model suggest that while the absence of βarr2 reduces the beneficial locomotor response of L‐DOPA, it enhances the manifestation of dyskinesias, presumably because it shifts the system to excessive G protein‐dependent signaling. As expected, in both the rodent and NHP model, over‐expression of βarr2 enhances the efficacy of forward locomotion (i.e on‐time) and at the same time reduces the manifestation of LIDs. Thus increasing activation of βarr2 either pharmacologically or genetically during L‐DOPA therapy may be an ideal way to overcome the motor deficits of Parkinsonian patients and ameliorate undesirable side‐effects of drug therapy. Grant Funding Source : Supported by the Michael J. Fox Foundation for PD research