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ID 110886
Title Alternative
線条体から黒質、淡蒼球に投射する中型有棘細胞のGαolfタンパクの発現はドパミン投与によって変化し、パーキンソン病モデルマウスにおけるL-ドーパ誘発性ジスキネジア発症に関与する
Striatal Gaolf Levels in L-DOPA-Induced Dyskinesia
Author
Keywords
olfactory type G-protein a subunit
dopamine
striatum
Parkinson’s disease
L-DOPA-induced dyskinesia
Content Type
Thesis or Dissertation
Description
The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), exerts powerful therapeutic effects but eventually generates L-DOPA-induced dyskinesia (LID) in patients with Parkinson’s disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein a subunit (Gaolf), a stimulatory GTP-binding protein encoded by the GNAL gene, is highly concentrated in the striatum, where it positively couples with dopamine D1 (D1R) receptor and adenosine A2A receptor (A2AR) to increase intracellular cAMP levels in MSNs. In the striatum, D1Rs are mainly expressed in the MSNs that form the striatonigral pathway, while D2Rs and A2ARs are expressed in the MSNs that form the striatopallidal pathway. Here, we examined the association between striatal Gaolf protein levels and the development of LID. We used a hemi-parkinsonian mouse model with nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Using quantitative immunohistochemistry (IHC) and a dual-antigen recognition in situ proximity ligation assay (PLA), we here found that in the dopamine-depleted striatum, there appeared increased and decreased levels of Gaolf protein in striatonigral and striatopallidal MSNs, respectively, after a daily pulsatile administration of L-DOPA. This leads to increased responsiveness to dopamine stimulation in both striatonigral and striatopallidal MSNs. Because Gaolf protein levels serve as a determinant of cAMP signal-dependent activity in striatal MSNs, we suggest that L-DOPA-induced changes in striatal Gaolf levels in the dopamine-depleted striatum could be a key event in generating LID.
Journal Title
Frontiers in Cellular Neuroscience
ISSN
16625102
Publisher
Frontiers Media S.A.
Volume
11
Start Page
26
Published Date
2017-02-10
Remark
内容要旨・審査要旨・論文本文の公開
本論文は, 著者Ryoma Morigakiの学位論文として提出され, 学位審査・授与の対象となっている。
Rights
Copyright © 2017 Morigaki, Okita and Goto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3097号
Diploma Number
医第1341号
Granted Date
2017-07-27
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital