title: Gadd45β ameliorates L-DOPA-induced dyskinesia in a Parkinson's disease mouse model.
abstract: The dopamine precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA) is currently the most efficacious pharmacotherapy for Parkinson's disease (PD). However, long-term L-DOPA treatment leads to the development of abnormal involuntary movements (AIMs) in patients and animal models of PD. Recently, involvement of growth arrest and DNA damage-inducible 45β (Gadd45β) was reported in neurological and neurobehavioral dysfunctions. However, little is known about the role of Gadd45β in the dopaminergic nigrostriatal pathway or L-DOPA-induced dyskinesia (LID). To address this issue, we prepared an animal model of PD using unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra of Gadd45β(+/+) and Gadd45β(-/-) mice. Dyskinetic symptoms were triggered by repetitive administration of L-DOPA in these 6-OHDA-lesioned mice. Whereas dopamine denervation in the dorsal striatum decreased Gadd45β mRNA, chronic L-DOPA treatment significantly increased Gadd45β mRNA expression in the 6-OHDA-lesioned striatum of wild-type mice. Using unilaterally 6-OHDA-lesioned Gadd45β(+/+) and Gadd45β(-/-) mice, we found that mice lacking Gadd45β exhibited long-lasting increases in AIMs following repeated administration of L-DOPA. By contrast, adeno-associated virus-mediated expression of Gadd45β in the striatum reduced AIMs in Gadd45β knockout mice. The deficiency of Gadd45β in LID increased expression of ΔFosB and c-Fos in the lesioned striatum 90 min after the last administration of L-DOPA following 11days of daily L-DOPA treatments. These data suggest that the increased expression of Gadd45β induced by repeated administration of L-DOPA may be beneficial in patients with PD.
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
authors.forename: Hye-Yeon
authors.initials: HY
authors.lastname: Park
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
authors.forename: Young-Kyoung
authors.initials: YK
authors.lastname: Ryu
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; College of Biosciences & Biotechnology, Chung-Nam National University, Daejeon 34134, Republic of Korea.
authors.forename: Tae-Shin
authors.initials: TS
authors.lastname: Park
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
authors.forename: Jun
authors.initials: J
authors.lastname: Go
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Choi
authors.affiliation: College of Biosciences & Biotechnology, Chung-Nam National University, Daejeon 34134, Republic of Korea.
authors.forename: Myungchull
authors.initials: M
authors.lastname: Rhee
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Daejeon 34113, Republic of Korea. Electronic address: chullee@kribb.re.kr.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Daejeon 34113, Republic of Korea. Electronic address: kskim@kribb.re.kr.
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000473:pathology; D007980:Levodopa / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D017868:Cyclic AMP-Dependent Protein Kinases; D007980:Levodopa; D016627:Oxidopamine; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins
keywords: Dyskinesia; GADD45β; L-DOPA; Parkinson's disease