title: Enhancing Beta-Catenin Activity via GSK3beta Inhibition Protects PC12 Cells against Rotenone Toxicity through Nurr1 Induction.
abstract: Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic (DA) neurons in the substantial nigra pars compacta. Increasing evidence showed that Wnt/β-catenin pathway and the orphan nuclear receptor Nurr1 play crucial roles in the survival and functional maintenance of DA neurons in the midbrain and GSK-3β antagonists LiCl and SB216763 were used to activate Wnt/β-catenin pathway experimentally. However, the detail mechanism underlying the neuroprotection against apoptosis on DA neuron is still unclear and the interaction between Wnt/β-catenin and Nurr1 remains undisclosed. In this study, using cell biological assay we investigated the function of Wnt/β-catenin and its crosstalk with Nurr1 on the course of PC12 cell degeneration in vitro. Our data showed that PC12 cell viability was inhibited by rotenone, but attenuated by GSK-3β antagonists LiCl or SB216763. The activity of Wnt/β-catenin pathway was deregulated on exposure of rotenone in a concentration-dependent manner. After the interference of β-catenin with siRNA, LiCl or SB216763 failed to protect PC12 cells from apoptosis by the rotenone toxicity. Our data confirmed that Wnt/β-catenin signaling activated by LiCl or SB216763 enhanced Nurr1 expression to 2.75 ± 0.55 and 4.06 ± 0.41 folds respectively compared with control detected by real-time PCR and the interaction of β-catenin with Nurr1 was identified by co-immunoprecipitate analysis. In conclusion, the data suggested that Wnt/β-catenin and Nurr1 are crucial factors in the survival of DA neurons, and the activation of Wnt/β-catenin pathway exerts protective effects on DA neurons partly by mean of a co-active pattern with Nurr1. This finding may shed a light on the potential treatment of Parkinson disease.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong 510080, China.|Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450052, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong 510080, China.
authors.forename: Luan
authors.initials: L
authors.lastname: Cen
authors.affiliation: Department of Blood Transfusion, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, 510900, China.
authors.forename: Shaogang
authors.initials: S
authors.lastname: Qu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong 510080, China.|Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong, 510080, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong 510080, China.
authors.forename: Mingshu
authors.initials: M
authors.lastname: Mo
authors.affiliation: Department of Blood Transfusion, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, 510900, China.
authors.forename: Junmin
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Neurology, Qilu Affiliated Hospital of Shandong University, Jinan, Shandong, 250001, China.
authors.forename: Congcong
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong 510080, China.
authors.forename: Yousheng
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Neurology, The Third Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Ann Romney Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, United States of America.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurology, The Third Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China.
authors.forename: Xinling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong 510080, China.|Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangdong, 510080, China.
authors.forename: Pingyi
authors.initials: P
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D012402:Rotenone / Q000494:pharmacology* / Q000633:toxicity; D014475:Uncoupling Agents / Q000494:pharmacology* / Q000633:toxicity; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D007211:Indoles; D008301:Maleimides; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D034741:RNA, Small Interfering; C417521:SB 216763; D014475:Uncoupling Agents; D051176:beta Catenin; D012402:Rotenone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D018021:Lithium Chloride