Down-regulation of P21-activated Serine/threonine Kinase 1 is Involved in Loss of Mesencephalic Dopamine Neurons

Overview

Journal Mol Brain

Publisher Biomed Central

Specialties Molecular Biology
Neurology

Date 2016 Apr 29

PMID 27121078

Citations 8

Authors

Hwanhee Kim

Jun-Young Oh

Sun-Lim Choi

Yeon-Ju Nam

Anna Jo

Ara Kwon

Eun-Young Shin

Eung-Gook Kim

Hyong Kyu Kim

Affiliations

Soon will be listed here.

Abstract

Background: Although the roles of p21-activated serine/threonine kinase 1 (PAK1) have been reported in some neurodegenerative diseases, details regarding neurodegeneration are still limited. Hence, we tried to determine the role of PAK1 and molecular mechanisms of neuronal death involved in neurodegeneration.

Results: Expression of a dominant-negative form of PAK1 (PAK1(H83,86L, K229R), PAK1-DN) decreased the cell viability and increased cell death induced by oxidative stress. Indeed, oxidative stress decreased the phosphorylation of PAK1 in neuroblastoma cells, cultured dopamine (DA) neurons, or rat midbrains. PAK1-DN reduced the level of Bcl-2 protein, through an ubiquitin/proteasome-dependent mechanism. The level of Bcl-2 may be regulated by PAK1-ERK signaling and/or PAK1, directly. Conversely, expression of an active form of PAK1 (PAK1(T423E), PAK1-CA) could recover both loss of DA neurons in the substantia nigra (SN) and behavioral defects in a 6-OHDA-induced hemiparkinsonian rat model.

Conclusions: Our data suggest that the oxidative stress-induced down-regulation of PAK1 activity could be involved in the loss of mesencephalic DA neurons through modulation of neuronal death, suggesting a novel role of PAK1 as a molecular determinant and mechanisms in the pathogenesis of Parkinson's disease.

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References

Hayashi M, Choi S, Rao B, Jung H, Lee H, Zhang D . Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron. 2004; 42(5):773-87. DOI: 10.1016/j.neuron.2004.05.003. View

Xue Y, Ren J, Gao X, Jin C, Wen L, Yao X . GPS 2.0, a tool to predict kinase-specific phosphorylation sites in hierarchy. Mol Cell Proteomics. 2008; 7(9):1598-608. PMC: 2528073. DOI: 10.1074/mcp.M700574-MCP200. View

Kumar A, Molli P, Pakala S, Nguyen T, Rayala S, Kumar R . PAK thread from amoeba to mammals. J Cell Biochem. 2009; 107(4):579-85. PMC: 2718766. DOI: 10.1002/jcb.22159. View

Koh C, Tan E, Manser E, Lim L . The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family. Curr Biol. 2002; 12(4):317-21. DOI: 10.1016/s0960-9822(02)00652-8. View

Tang Y, Zhou H, Chen A, Pittman R, Field J . The Akt proto-oncogene links Ras to Pak and cell survival signals. J Biol Chem. 2000; 275(13):9106-9. DOI: 10.1074/jbc.275.13.9106. View

Ho S, Hsu C, Pawlak C, Tikhonova M, Lai T, Amstislavskaya T . Effects of ceftriaxone on the behavioral and neuronal changes in an MPTP-induced Parkinson's disease rat model. Behav Brain Res. 2014; 268:177-84. DOI: 10.1016/j.bbr.2014.04.022. View

Vadlamudi R, Adam L, Wang R, Mandal M, Nguyen D, Sahin A . Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem. 2000; 275(46):36238-44. DOI: 10.1074/jbc.M002138200. View

Dimmeler S, Breitschopf K, Haendeler J, Zeiher A . Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link between the apoptosome and the proteasome pathway. J Exp Med. 1999; 189(11):1815-22. PMC: 2193081. DOI: 10.1084/jem.189.11.1815. View

Tabares-Seisdedos R, Dumont N, Baudot A, Valderas J, Climent J, Valencia A . No paradox, no progress: inverse cancer comorbidity in people with other complex diseases. Lancet Oncol. 2011; 12(6):604-8. DOI: 10.1016/S1470-2045(11)70041-9. View

10.

Deumens R, Blokland A, Prickaerts J . Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol. 2002; 175(2):303-17. DOI: 10.1006/exnr.2002.7891. View

11.

Salmon P, Kindler V, Ducrey O, Chapuis B, Zubler R, Trono D . High-level transgene expression in human hematopoietic progenitors and differentiated blood lineages after transduction with improved lentiviral vectors. Blood. 2000; 96(10):3392-8. View

12.

Jeong J, Nam Y, Kim S, Kim E, Jeong J, Kim H . The transport of Staufen2-containing ribonucleoprotein complexes involves kinesin motor protein and is modulated by mitogen-activated protein kinase pathway. J Neurochem. 2007; 102(6):2073-2084. DOI: 10.1111/j.1471-4159.2007.04697.x. View

13.

Zhan Q, Ge Q, Ohira T, Van Dyke T, Badwey J . p21-activated kinase 2 in neutrophils can be regulated by phosphorylation at multiple sites and by a variety of protein phosphatases. J Immunol. 2003; 171(7):3785-93. DOI: 10.4049/jimmunol.171.7.3785. View

14.

Cory S, Huang D, Adams J . The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003; 22(53):8590-607. DOI: 10.1038/sj.onc.1207102. View

15.

Luo S, Mizuta H, Rubinsztein D . p21-activated kinase 1 promotes soluble mutant huntingtin self-interaction and enhances toxicity. Hum Mol Genet. 2007; 17(6):895-905. DOI: 10.1093/hmg/ddm362. View

16.

Golstein P . Controlling cell death. Science. 1997; 275(5303):1081-2. DOI: 10.1126/science.275.5303.1081. View

17.

Hartmann A, Michel P, Troadec J, Mouatt-Prigent A, Faucheux B, Ruberg M . Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson's disease?. J Neurochem. 2001; 76(6):1785-93. DOI: 10.1046/j.1471-4159.2001.00160.x. View

18.

Adam L, Vadlamudi R, Mandal M, Chernoff J, Kumar R . Regulation of microfilament reorganization and invasiveness of breast cancer cells by kinase dead p21-activated kinase-1. J Biol Chem. 2000; 275(16):12041-50. DOI: 10.1074/jbc.275.16.12041. View

19.

Kumar R, Gururaj A, Barnes C . p21-activated kinases in cancer. Nat Rev Cancer. 2006; 6(6):459-71. DOI: 10.1038/nrc1892. View

20.

Harms A, Barnum C, Ruhn K, Varghese S, Trevino I, Blesch A . Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson's disease. Mol Ther. 2010; 19(1):46-52. PMC: 3017447. DOI: 10.1038/mt.2010.217. View