α-Synuclein Protects against Oxidative Stress via Inactivation of the c-Jun N-terminal Kinase Stress-signaling Pathway in Neuronal Cells

Abstract

The expression of ␣-synuclein, a synaptic molecule implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Lewy body disease is increased upon injury to the nervous system, indicating that it might play a role in regeneration and plasticity; however, the mechanisms are unclear. Because c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, plays an important role in stress response, the main objective of the present study was to better understand the involvement of this pathway in the signaling responses associated with resistance to injury in cells expressing ␣-synuclein. Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD) 1 are characterized by selective neuronal and synaptic damage in cortical and subcortical regions resulting in cognitive and motor impairment (1). The mechanisms leading to neurodegeneration in these disorders are unclear; however, recent studies suggest that abnormal aggregation of misfolded neuronal proteins might play a central role (2, 3). Although in Alzheimer's disease intracellular (4, 5) and extracellular aggregation of amyloid ␤-protein (5) has been implicated in PD, intraneuronal aggregation of misfolded ␣-synuclein (6 -8) has been suggested to be involved in the pathogenesis of the neurodegenerative process. In supporting a role of misfolded ␣-synuclein in the pathogenesis of PD, previous studies show that missense mutations that accelerates ␣-synuclein aggregation (9) are associated with familial PD (10, 11). Furthermore, Lewy bodies that are intraneuronal inclusions found in patients with parkinsonism are primarily composed of misfolded ␣-synuclein (6 -8), and overexpression of ␣-synuclein in transgenic mice (12) and Drosophila (13) resulted in Lewy body-like formation associated with degeneration of dopaminergic neurons. ␣-Synuclein is an abundant synaptic protein that is a member of the synuclein family of peptides that includes ␣-, ␤-, and ␥-synuclein as well as synoretin (14,15). The physiological roles of these proteins are unclear, although they might play an important role in neuroplasticity and in response to neuronal cell damage (14, 16). In support of this possibility, recent studies show that ␣-synuclein expression is increased in models of developmental-targeted injury (17,18). In this model, up-regulation of ␣-synuclein at the mRNA level is associated with an increase number of neurons expressing ␣-synuclein, and at the cellular level, ␣-synuclein is almost exclusively expressed in normal neurons rather than in apoptotic cells (18). Moreover, during development, ␣-synuclein expression is up-regulated (19), and the expression of this synaptic molecule is not further up-regulated during the period of natural cell death (17,18). In neuronal cell lines, overexpression of wild type ␣-synuclein protects against oxidative stress (20). In contrast, neuronal cell lines expressing ␣-synuclein that contains mutations (A30P and A53T) associated with familial Parkinsonism and...

2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production

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“…In contrast, transfection of cells with a vector encoding a dominant-negative form of JNK1 reduced apoptosis in 2-Me-treated cells as compared to cells transfected with an empty pcDNA vector (Figure 9b). This result (Benhar et al, 2001;Aoki et al, 2002;Hashimoto et al, 2002). We therefore investigated whether generation of H 2 O 2 that occurred in 2-Me-treated cells was responsible for JNK activation.…”

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

“…[25][26][27] In this study, we extended these observations by demonstrating the presence of IB1/JIP-1 in human AD brain colocalized with JNK and phosphorylated tau proteins in neurofibrillary tangles. IB1/JIP-1 interacts with many cellular components including the reelin receptor ApoER2, LRP, a-synuclein, 190 RhoGEF, kinesin and APP [13][14][15][16][17][18]40 . In mice, the selective disruption of both ApoER2 and VLDL receptor (VLDLR) induced a drastic phenotype associated with abnormal neuronal migration and development.…”

β-Synuclein Regulates Akt Activity in Neuronal Cells

“…The experiments were done in quadruplicate and statistically analyzed by Student's t test. Trypan blue exclusion assays were performed as previously described (23).…”

“…The precise physiological role of ␣-and ␤-synuclein in synaptic plasticity is not completely understood. However, recent studies have demonstrated that although ␣-synuclein is aggregated under oxidative stress conditions, ␤-synuclein does not aggregate to form amyloid fibrils, and it is capable of blocking ␣-synuclein aggregation and potentially protecting cells from the neurotoxic effects of ␣-synuclein oligomers (23,24). The mechanisms by which ␣-synuclein accumulation might lead to neurodegeneration are currently under investigation.…”