p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism
Abstract
Parkinson’s disease (PD) is symptomatically treated with levodopa (L-DOPA), but this treatment often results in disabling dyskinesias. Subchronic L-DOPA increases striatal levels of adaptor protein, p11. Using experimental mouse models of Parkinsonism, we report here that global p11 knockout mice show reduced therapeutic responses to L-DOPA on rotational motor sensitization, but also develop less L-DOPA–induced dyskinesias. Mice lacking p11 in dopamine D2R-containing neurons have reduced response to L-DOPA on the therapeutic parameters, but develop dyskinetic side effects. In contrast, mice lacking p11 in dopamine D1R-containing neurons exhibit rotational responses toward L-DOPA, but develop less dyskinesia. These results imply that reductions of p11 in D1R-containing cells may be a viable therapy against L-DOPA–induced dyskinesias.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 19, 2016
- Source ID
- 10.1073/pnas.1524303113
Entities
People
- Alexandra Alvarsson
- Michael G. Kaplitt
- Nicoletta Schintu
- Paul Greengard
- Per Svenningsson
- Roberta Marongiu
- Xiaoqun Zhang
Organizations
- Fisher Center for Alzheimer's Research Foundation
- Swedish Research Council
- The Rockefeller University
- United States Department of Defense
- Weill Cornell Medicine