Effects of Mutant Huntingtin on mGluR5-Mediated Dual Signaling Pathways: Implications for Therapeutic Interventions |
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Authors: | Shan-Shan Huang Jun He Dong-Ming Zhao Xiao-Yuan Xu Hui-Ping Tan He Li |
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Institution: | (1) Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China;(2) Department of Orthopedics, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China;(3) Department of Histology and Embryology, Jiujiang Medical College, Jiangxi, 332000, China |
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Abstract: | Glutamate excitotoxicity is thought to play an important role in Huntington’s disease (HD), which is caused by a polyglutamine
expansion in the HD protein huntingtin (htt). Overactivation of group I metabotropic glutamate receptors (mGluRs), which include
mGluR1 as well as mGluR5 and are coupled via phospholipase C to the inositol phosphate pathway, is found to be involved in
mutant htt-mediated neurotoxicity. However, activation of mGluR5 also leads to neuronal protection. Here, we report that mutant
htt can activate both mGluR5-mediated ERK and JNK signaling pathways. While increased JNK signaling causes cell death, activation
of ERK signaling pathway is protective against cell death. Expression of mutant htt in cultured cells causes greater activation
of JNK than ERK. These findings suggest that selective inhibition of the JNK signaling pathway may offer an effective therapeutic
approach for reducing htt-mediated excitotoxicity. |
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