M-L Martin-Négrier et al. in Neurobiology of Disease
Dopamine–induced proteasome activity impairment in L-Dopa–induced dyskinesia: An assembly story !
May 18, 2015
D1 dopamine receptor stimulation impairs striatal proteasome activity in Parkinsonism through 26S proteasome disassembly. Barroso-Chinea P, Thiolat ML, Bido S, Martinez A, Doudnikoff E, Baufreton J, Bourdenx M, Bloch B, Bezard E, Martin-Negrier ML.
Neurobiol Dis. 2015 Mar 10;78:77-87. doi: 10.1016/j.nbd.2015.02.024 –
Dyskinesia, a debilitating complication of L-dopa therapy for Parkinson’s disease, are partly explained by a dysregulation of dopamine D1 Receptor (D1R) trafficking leading to a pathological anchoring of D1R at the plasma membrane. We have shown previously that such anchoring is partially due to a decreased proteasomal activity and that specific stimulation of D1R induced a decrease in proteasomal activity in a dopamine depleted environment (1).
In this study, we investigated the molecular mechanisms by which dopaminergic stimulation affects striatal proteasome activity. To reach this goal, we used in vitro (striatal cultured neurons), ex vivo (striatal slices) and in vivo models of striatal dopamine depletion (reserpine treated mice model). We showed that D1R-stimulated DA-depleted mice presented a decrease of striatal proteasome chymotrypsine-like activity without change in transcription or translation of proteasome subunits. Surprisingly, proteasome subunits immuno-detection showed an increase of the immunoreactivity without neuronal massive subunits relocalization. Active 26S proteasome consists in a 20S core structure containing the enzyme active sites and a 19S cap structures that regulate the activity of the complex. We wondered whether a 26S proteasome disassembly could explain the activity decrease observed after D1R stimulation. We studied proteasome subunits assembly by two-dimensional Clear Native (CN)/SDS gel. We observed a decrease in active 26S particles relative to free 20S particles after D1R stimulation in dopamine–depleted mice consistent with the observed catalytic activity decrease. Moreover we hypothesized that such proteasome disassembly could explain the increased of proteasomal subunits immunodetection through epitopes unmasking on free subunits.
(1) Berthet A, Bezard E, Porras G, Fasano S, Barroso-Chinea P, Dehay B, Martinez A, Thiolat ML, Nosten M, Giros B, Baufreton J, Li Q, Bloch B and Martin-Negrier ML. L-dopa impairs proteasome activity in parkinsonism through D1 dopamine receptor. J Neurosci, 2012, 32(2):681-91
Assistant Professor – Hospital practitioner – MD-PhD
Affiliated with the lab: Neurodegenerative Diseases Institute of Erwan Bezard
Marie-Laure Martin-Negrier MD, PhD / marie-*protected email*
Last update on 18.05.2015