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Title 

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

Authors 

Hye-Yeon ParkYoung-Kyoung RyuYong-Hoon KimTae-Shin ParkJun GoJung Hwan HwangDong Hee ChoiM RheeChul Ho LeeKyoung Shim Kim

Publisher 

Elsevier

Issue Date 

2016

Citation 

Neurobiology of Disease, vol. 89, no. 0, pp. 169-179

Keywords 

DyskinesiaGADD45βL-DOPAParkinson's disease

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 11 days 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.

ISSN 

0969-9961

Link 

http://dx.doi.org/10.1016/j.nbd.2016.02.013

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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