l-DOPA Impairs Proteasome Activity in Parkinsonism through D₁Dopamine 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.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Thus, in the MPTP-lesioned NHP killed 1 hour after the last dose of L-DOPA, in nondyskinetic animals, D 1 receptors were recruited at the synaptic membrane of striatal neurons, whereas they were recruited at both the synaptic membrane and the cytoplasmic compartment in dyskinetic animals . Hypoactivity of the 20S proteasomal subunit of striatal medium spiny neurons could be an important determinant in this altered distribution of D 1 receptors in dyskinesia (Berthet et al, 2012). Indeed, hypoactivity of the 20S proteasomal subunit would impair degradation of D 1 receptors, which might account for their recruitment at both the synaptic membrane and the cytoplasmic compartment (Berthet et al, 2012).…”

“…Hypoactivity of the 20S proteasomal subunit of striatal medium spiny neurons could be an important determinant in this altered distribution of D 1 receptors in dyskinesia (Berthet et al, 2012). Indeed, hypoactivity of the 20S proteasomal subunit would impair degradation of D 1 receptors, which might account for their recruitment at both the synaptic membrane and the cytoplasmic compartment (Berthet et al, 2012).…”

Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA–Induced Dyskinesia

“…Experimental parkinsonism was achieved with a unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle as previously described (6,(16)(17)(18). Surgeries were conducted under isoflurane anesthesia.…”

“…On the last day, baseline AIMs were scored as previously described (6,8,(16)(17)(18) using a validated rating scale assessing three items (axial, forelimb, orolingual dyskinesia) rated from 0 (absent) to 4 (continuous, severe, uninterrupted by sensory distraction) (21) to obtain a composite score (maximum 12 points). Ratings lasted 1 minute per rat at 30, 60, 90, and 120 minutes post L-dopa.…”

“…From the fourth day, all rats received a daily 6 mg/kg L-dopa injection and AIMs were scored. Because 6 mg/kg L-dopa induces marked dyskinesia in rats (16,22), possibly reaching plateau levels, a 4 mg/kg dose was further tested. AIMs and rotation scores were then stabilized with 4 mg/kg L-dopa during 5 consecutive days with a baseline rating on the last day.…”