title: Inhibition of adenylyl cyclase type 5 prevents L-DOPA-induced dyskinesia in an animal model of Parkinson's disease.
abstract: The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) is widely used as a therapeutic choice for the treatment of patients with Parkinson's disease. However, the long-term use of L-DOPA leads to the development of debilitating involuntary movements, called L-DOPA-induced dyskinesia (LID). The cAMP/protein kinase A (PKA) signaling in the striatum is known to play a role in LID. However, from among the nine known adenylyl cyclases (ACs) present in the striatum, the AC that mediates LID remains unknown. To address this issue, we prepared an animal model with unilateral 6-hydroxydopamine lesions in the substantia nigra in wild-type and AC5-knock-out (KO) mice, and examined behavioral responses to short-term or long-term treatment with L-DOPA. Compared with the behavioral responses of wild-type mice, LID was profoundly reduced in AC5-KO mice. The behavioral protection of long-term treatment with L-DOPA in AC5-KO mice was preceded by a decrease in the phosphorylation levels of PKA substrates ERK (extracellular signal-regulated kinase) 1/2, MSK1 (mitogen- and stress-activated protein kinase 1), and histone H3, levels of which were all increased in the lesioned striatum of wild-type mice. Consistently, FosB/ΔFosB expression, which was induced by long-term L-DOPA treatment in the lesioned striatum, was also decreased in AC5-KO mice. Moreover, suppression of AC5 in the dorsal striatum with lentivirus-shRNA-AC5 was sufficient to attenuate LID, suggesting that the AC5-regulated signaling cascade in the striatum mediates LID. These results identify the AC5/cAMP system in the dorsal striatum as a therapeutic target for the treatment of LID in patients with Parkinson's disease.
authors.affiliation: Laboratory Animal Resource Center and Departments of Food and Nutrition and.
authors.forename: Hye-Yeon
authors.initials: HY
authors.lastname: Park
authors.affiliation: Laboratory Animal Resource Center and.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kang
authors.affiliation: Laboratory Animal Resource Center and.
authors.forename: Young
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Laboratory Animal Resource Center and Bioscience of Biotechnology, Chung-Nam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Tae-Shin
authors.initials: TS
authors.lastname: Park
authors.affiliation: Laboratory Animal Resource Center and.
authors.forename: Young-Kyoung
authors.initials: YK
authors.lastname: Ryu
authors.affiliation: Laboratory Animal Resource Center and.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Hwang
authors.affiliation: Laboratory Animal Resource Center and.
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: BioNanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea, University of Science and Technology, Daejeon 305-850, Republic of Korea, and.
authors.forename: Bong-Hyun
authors.initials: BH
authors.lastname: Chung
authors.affiliation: Laboratory Animal Resource Center and.
authors.forename: Ki-Hoan
authors.initials: KH
authors.lastname: Nam
authors.affiliation: Departments of Food and Nutrition and.
authors.forename: Mee-Ree
authors.initials: MR
authors.lastname: Kim
authors.affiliation: Laboratory Animal Resource Center and University of Science and Technology, Daejeon 305-850, Republic of Korea, and.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Brain & Cognitive Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Pyung-Lim
authors.initials: PL
authors.lastname: Han
authors.affiliation: Laboratory Animal Resource Center and University of Science and Technology, Daejeon 305-850, Republic of Korea, and kskim@kribb.re.kr.
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000201:enzymology* / Q000517:prevention & control; D007150:Immunohistochemistry; D007980:Levodopa / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020734:Parkinsonian Disorders / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000978:Antiparkinson Agents; D007980:Levodopa; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V
keywords: Parkinson's disease; adenylyl cyclase; dyskinesia; l-DOPA