Down-regulation of p21-activated serine/threonine kinase 1 is involved in loss of mesencephalic dopamine neurons.
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.



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.



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.
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, 28644, The Republic of Korea.
Hwanhee
H
Kim
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, 28644, The Republic of Korea.
Jun-Young
JY
Oh
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, 28644, The Republic of Korea.
Sun-Lim
SL
Choi
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, 28644, The Republic of Korea.
Yeon-Ju
YJ
Nam
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, 28644, The Republic of Korea.
Anna
A
Jo
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, 28644, The Republic of Korea.
Ara
A
Kwon
Department of Medicine and Biochemistry, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, 28644, The Republic of Korea.
Eun-Young
EY
Shin
Department of Medicine and Biochemistry, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, 28644, The Republic of Korea.
Eung-Gook
EG
Kim
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, 28644, The Republic of Korea. hkkim69@chungbuk.ac.kr.|Department of Medicine and Microbiology, College of Medicine, Chungbuk National University, Chungdae-ro 1, Seowon-gu, Cheongju, 28644, The Republic of Korea. hkkim69@chungbuk.ac.kr.
Hyong Kyu
HK
Kim
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008636:Mesencephalon / Q000473:pathology*; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D016627:Oxidopamine; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D054462:p21-Activated Kinases / Q000378:metabolism*
D065095:Calcineurin Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016627:Oxidopamine; D054462:p21-Activated Kinases; D019703:Calcineurin
Apoptosis; Bcl-2; Neurodegeneration; PAK1; Parkinson’s disease