Skip to Main content Skip to Navigation
Journal articles

L-DOPA Impairs Proteasome Activity in Parkinsonism through D1 Dopamine Receptor

Abstract : Aberrant membrane localization of dopamine D(1) receptor (D1R) is associated with L-DOPA-induced dyskinesia (LID), a major complication of L-DOPA treatment in Parkinson's disease (PD). Since the proteasome plays a central role in modulating neuronal response through regulation of neurotransmitter receptor intraneuronal fate, we hypothesized that the ubiquitine-proteasome proteolytic pathway could be impaired in LID. Those LIDs are actually associated with a striatum-specific decrease in proteasome catalytic activity and accumulation of polyubiquitinated proteins in experimental rodent and monkey parkinsonism. We then demonstrated that such decreased proteasome catalytic activity (1) results from D1R activation and (2) feed-back the D1R abnormal trafficking, i.e., its exaggerated cell surface abundance. We further showed that the genetic invalidation of the E3 ubiquitin-protein ligase parkin PD gene leads to exaggerated abnormal involuntary movements compared with wild-type mice. We thus established in an unprecedented series of experimental models that impairment of the ubiquitine-proteasome system at specific nodes (E3 ligase parkin, polyubiquitination, proteasome catalytic activity) leads to the same phenomenon, i.e., aberrant behavioral response to dopamine replacement therapy in PD, highlighting the intimate interplay between dopamine receptor and proteasome activity in a nondegenerative context.
Document type :
Journal articles
Complete list of metadata

Cited literature [59 references]  Display  Hide  Download
Contributor : Benjamin Dehay Connect in order to contact the contributor
Submitted on : Tuesday, January 14, 2020 - 3:04:37 PM
Last modification on : Monday, June 27, 2022 - 3:48:40 AM
Long-term archiving on: : Wednesday, April 15, 2020 - 8:22:44 PM


Publisher files allowed on an open archive




Amandine Berthet, Erwan Bézard, Gregory Porras, Stefania Fasano, Pedro Barroso-Chinea, et al.. L-DOPA Impairs Proteasome Activity in Parkinsonism through D1 Dopamine Receptor. Journal of Neuroscience, Society for Neuroscience, 2012, 32 (2), pp.681-691. ⟨10.1523/JNEUROSCI.1541-11.2012⟩. ⟨inserm-02439205⟩



Record views


Files downloads