연구논문

세부과제번호 2013M3A9D5072559 단계 1단계 1차년도
세부과제명 마우스기본표현형 고속분석 기반구축운용 공동 유/무 N
SCI여부 Y 게재년월 2014-08
논문제목 Inhibition of Adenylyl Cyclase Type 5 Prevents L-DOPA-Induced Dyskinesia in an Animal Model of Parkinson`s Disease
총저자명 Park, Hye-Yeon; Kang, Young-Mi; Kang, Young; Park, Tae-Shin; Ryu, Young-Kyoung; Hwang, Jung-Hwan; Kim, Yong-Hoon; Chung, Bong-Hyun; Nam, Ki-Hoan; Kim, Mee-Ree; Lee, Chul-Ho; Han, Pyung-Lim; Kim, Kyoung-Shim;
학술지명 JOURNAL OF NEUROSCIENCE 게재권(호) 34(35)
저널구분 국외 페이지수 6.747
참여연구원 - 연구책임자 남기환
과제기여도 25 PMID
사사기관수 IF (년도)
제1저자 교신저자
공동저자
초록
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.
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