Gadd45β ameliorates L-DOPA-induced dyskinesia in a Parkinson's disease mouse model

Authors
Park HY, Ryu YK, Kim YH, Park TS, Go J, Hwang JH, Choi DH, Rhee M, Lee CH, Kim KS

Lab
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea

Journal
Neurobiol Dis.

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 90min 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.