title: 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 α-synuclein (α-Syn) or empty vector (Vec) control. We report that α-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 α-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 α-Syn-expressing cells upon Cd exposure. Analysis of the mitochondrial mediated apoptotic pathway showed greater activation of caspase-9 and caspase-3 in α-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 α-Syn-expressing cells without altering native PKCδ protein levels in both Vec control and α-Syn lines. In addition, we show decreased basal metallothionein-3 protein expression in α-Syn-expressing cells. Co-treatment with N-acetyl-L-cysteine was sufficient to attenuate and abolish the α-Syn × Cd-induced cytotoxicity. Collectively, these results demonstrate that α-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.
authors.affiliation: Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH, 44074, USA.
authors.forename: Weelic
authors.initials: W
authors.lastname: Chong
authors.affiliation: Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH, 44074, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jiménez
authors.affiliation: Marine Chemistry and Geochemistry Department, Woods Hole Oceanographic Institution, Woods Hole, MA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: McIIvin
authors.affiliation: Marine Chemistry and Geochemistry Department, Woods Hole Oceanographic Institution, Woods Hole, MA, USA.
authors.forename: Mak A
authors.initials: MA
authors.lastname: Saito
authors.affiliation: Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH, 44074, USA. Gunnar.Kwakye@oberlin.edu.
authors.forename: Gunnar F
authors.initials: GF
authors.lastname: Kwakye
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019256:Cadmium Chloride / Q000633:toxicity*; D020169:Caspases / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002461:Cell Line, Transformed; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051844:alpha-Synuclein / Q000378:metabolism / Q000494:pharmacology*; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D000111:Acetylcysteine; D019256:Cadmium Chloride; D020169:Caspases; D027682:Cation Transport Proteins; D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D051058:Oncogene Protein v-akt; D051844:alpha-Synuclein; D000099236:Solute Carrier Family 11, Member 2
keywords: Antioxidants; Cadmium; Caspase; Metal transport; Neurotoxicity; Oxidative stress; Parkinson’s disease; α-Synuclein