α‐Synuclein regulates neuronal survival via Bcl‐2 family expression and PI3/Akt kinase pathway

Abstract

Alpha-synuclein (alpha-SN) is a ubiquitous protein that is especially abundant in the brain and has been postulated to play a central role in the pathogenesis of Parkinson's disease, Alzheimer's disease, and other neurodegenerative disorders. However, little is known about the neuronal functions of alpha-SN and the molecular and cellular mechanisms underlying neuronal loss. Here, we show that alpha-SN plays dual roles of neuroprotection and neurotoxicity depending on its concentration or level of expression. At nanomolar concentrations, a-SN protected neurons against serum deprivation, oxidative stress, and excitotoxicity through the PI3/Akt signaling pathway, and its protective effect was increased by Bcl-2 overexpression. Conversely, at both low micromolar and overexpressed levels in the cell, alpha-SN resulted in cytotoxicity. This might be related to decreased Bcl-xL expression and increased bax expression, which is subsequently followed by cytochrome c release and caspase activation and also by microglia-mediated inflammatory responses via the NFkappaB and mitogen-activated protein kinase pathways.

Endogenous α-Synuclein Is Induced by Valproic Acid through Histone Deacetylase Inhibition and Participates in Neuroprotection against Glutamate-Induced Excitotoxicity

“…At present, it is unclear as to whether the neuroprotective effects are mediated by secretion of upregulated ␣-syn to act on the cell surface or are attributable to a direct action of intracellular ␣-syn on cellular machinery. It has been reported that exogenous ␣-syn at relatively low concentrations activates the cell-survival factor Akt and induces the cytoprotective protein Bcl-X L but downregulates the proapoptotic protein Bax in PC12 cells, and these effects are reversed by raising the concentrations of ␣-syn to a toxic level (Seo et al, 2002). In GT-17 cells, ␣-syn transfection also suppresses H 2 O 2 -induced activation of JNK and cell death, and the JNK inactivation is accompanied by increased expression and activity of a JNK-interacting protein JIP, the scaffold protein for the JNK signaling pathway (M. .…”

“…For example, exogenous or overexpressed ␣-syn protects against multiple insults in cultured neurons (Seo et al, 2002;Alves da Costa et al, 2000Jensen et al, 2003). Transgenic expression of ␣-syn prevents paraquat-induced degeneration of nigrostriatal dopaminergic neurons and cysteine-string protein-␣-induced nerve terminal injury (Manning-Bog et al, 2003;Chandra et al, 2005).…”

“…Transgenic expression of ␣-syn prevents paraquat-induced degeneration of nigrostriatal dopaminergic neurons and cysteine-string protein-␣-induced nerve terminal injury (Manning-Bog et al, 2003;Chandra et al, 2005). The neuroprotective mechanisms of ␣-syn appear to include the activation of phosphatidylinositol 3-kinase/ Akt, suppression of p53 and c-Jun-N-terminal kinase (JNK) signaling, as well as the induction of neuroprotective/neurotrophic factors (Seo et al, 2002;Alves da Costa et al, 2002;M. Hashimoto et al, 2002;Manning-Bog et al, 2003;Albani et al, 2004;Kohno et al, 2004).…”

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

“…16 α-Syn has been shown to be internalized via GM1 and hitherto unknown protein receptors via a lipid raft-dependent endocytosis mechanism, 18 suggesting that cytosolic α-syn can be released from cells and taken up by other cells. In addition to studies of its release and uptake, extracellular α-syn has been reported to have effects on neurotoxicity 15,19,20 and inflammation. 14,18,[21][22][23][24] Recent observations that the transplants grafted into the brain of PD patients displayed Lewy bodies 25,26 were considered to be connected with Braak et al's proposal that Lewy body pathology spreads from one brain area to another according to a stereotypic pattern in specific stages.…”

Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson's disease

“…One possibility is that the PI3K/Akt signaling pathway might act through modulation of Bcl-2 expression, and it has been shown that expression of Bcl-2 is induced by a-synuclein [21]. Supporting this possibility, several studies have demonstrated that activated Akt stimulated changes in Bcl-2 and Bax expression and showed anti-apoptotic effects in many different cell types, including hippocampal neurons and PC12 cells [22,23].…”