Abstract
BackgroundAlthough 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.ResultsExpression of a dominant-negative form of PAK1 (PAK1H83,86L, 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 (PAK1T423E, 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0230-6) contains supplementary material, which is available to authorized users.
Highlights
The roles of p21-activated serine/threonine kinase 1 (PAK1) have been reported in some neurodegenerative diseases, details regarding neurodegeneration are still limited
Down-regulation of PAK1 activity increases apoptotic cell death In order to determine the role of PAK1 in cell proliferation and viability, we constructed the cell lines stably expressing wild-type PAK1 (WT), constitutively active PAK1 mutant (PAK1-constitutively active form (CA), PAK1T423E), dominantnegative PAK1 mutant (PAK1-dominant-negative form (DN), PAK1H83,86L, K299R) [19, 20], or GFP using a neuroblastoma cell line, SHSY5Y cell line, lentiviral vector, and fluorescenceactivated cell sorting
Apoptotic cell death in PAK1CA expressing cells was decreased compared to that in the control cells, but the difference was not significant. These results indicate that PAK1 activity could regulate apoptotic cell death in neuroblastoma cells
Summary
The roles of p21-activated serine/threonine kinase 1 (PAK1) have been reported in some neurodegenerative diseases, details regarding neurodegeneration are still limited. The p21-activated serine/threonine kinase 1 (PAK1) has a role in a variety of cellular functions like cell motility, cell cycle, survival, and even death. Apoptosis (type I cell death), known as programmed cell death, is a finely regulated mechanism initiated by signaling in response to a variety of stresses cells. It has important roles in development and tissue homeostasis in multicellular organisms. The susceptibility to apoptotic cell death is dependent on the relative level of anti-apoptotic proteins of Bcl-2 family members (Bcl-2, Bcl-xL, Mcl-1) to that of proapoptotic proteins of the family (Bad, Bax, Bak, Bok) or the interaction of each protein.
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