L-DOPA impairs proteasome activity in parkinsonism through D 1 dopamine receptor

A. Berthet, E. Bezard, G. Porras, S. Fasano, P. Barroso-Chinea, B. Dehay, A. Martinez, M.-L. Thiolat, M. Nosten-Bertrand, B. Giros, J. Baufreton, Q. Li, B. Bloch, M.-L. Martin-Negrier
Journal of Neuroscience. 2012-01-11; 32(2): 681-691
DOI: 10.1523/JNEUROSCI.1541-11.2012

Read on PubMed

1. J Neurosci. 2012 Jan 11;32(2):681-91. doi: 10.1523/JNEUROSCI.1541-11.2012.

L-DOPA impairs proteasome activity in parkinsonism through D1 dopamine receptor.

Berthet A(1), Bezard E, Porras G, Fasano S, Barroso-Chinea P, Dehay B, Martinez
A, Thiolat ML, Nosten-Bertrand M, Giros B, Baufreton J, Li Q, Bloch B,
Martin-Negrier ML.

Author information:
(1)Université Victor Segalen-Bordeaux 2, Centre National de la Recherche
Scientifique, Institute of Neurodegenerative Diseases, 33076 Bordeaux, France.

Comment in
Mov Disord. 2012 May;27(6):706.

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.

DOI: 10.1523/JNEUROSCI.1541-11.2012
PMID: 22238104 [Indexed for MEDLINE]

Know more about