α-Synuclein Enhances Cadmium Uptake and Neurotoxicity via Oxidative Stress and Caspase Activated Cell Death Mechanisms in a Dopaminergic Cell Model of Parkinson’s Disease

Abstract

This study examined the role of alpha-synuclein in regulating cadmium (Cd)-induced neurotoxicity using the N27 dopaminergic neuronal model of Parkinson's disease (PD) that stably expresses wild-type human alpha-synuclein (alpha-Syn) or empty vector (Vec) control. We report that alpha-Syn significantly increased Cd-induced cytotoxicity as compared to Vec control cells upon 24 h exposure. To explore the cellular mechanisms, we examined oxidative stress, caspase activation, and Cd uptake and intracellular accumulation. Expression of alpha-Syn coupled with Cd-induced cytotoxicity increased oxidative stress. Inductively coupled plasma-mass spectrometry (ICP-MS) revealed an increase in Cd uptake and intracellular accumulation in alpha-Syn-expressing cells upon Cd exposure. Analysis of the mitochondrial mediated apoptotic pathway showed greater activation of caspase-9 and caspase-3 in alpha-Syn cells. To functionally evaluate the role of metal transporters in the altered Cd phenotype, we examined Cd toxicity in the presence of nontoxic levels of divalent manganese Mn(II) and iron Fe(II). Co-treatment with Fe(II) or Mn(II) did not significantly attenuate Cd-induced cytotoxicity. We report that Cd exposure decreased the divalent metal transporter 1 and Akt protein levels in the alpha-Syn-expressing cells without altering native PKC delta protein levels in both Vec control and alpha-Syn lines. In addition, we show decreased basal metallothionein-3 protein expression in alpha-Syn-expressing cells. Co-treatment with N-acetyl-l-cysteine was sufficient to attenuate and abolish the alpha-Syn x Cd-induced cytotoxicity. Collectively, these results demonstrate that alpha-Syn exhibits neurotoxic properties upon acute Cd exposure to cause cell death by causing oxidative stress, increasing Cd uptake, altering caspase-9 and caspase-3 activation, and diminishing the neuroprotective effect of Akt in a dopaminergic neuronal model of PD.

Publisher

Springer Verlag

Publication Date

8-1-2017

Publication Title

Neurotoxicity Research

Department

Neuroscience

Document Type

Article

DOI

https://dx.doi.org/10.1007/s12640-017-9725-x

Keywords

alpha-Synuclein, Cadmium, Parkinson's disease, Oxidative stress, Caspase, Antioxidants, Metal transport, Neurotoxicity

Language

English

Format

text

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