The Divalent Metal Transporter Homologues SMF-1/2 Mediate Dopamine Neuron Sensitivity in Caenorhabditis elegans Models of Manganism and Parkinson Disease

Abstract

Parkinson disease (PD) and manganism are characterized by motor deficits and a loss of dopamine (DA) neurons in the substantia nigra pars compacta. Epidemiological studies indicate significant correlations between manganese exposure and the propensity to develop PD. The vertebrate divalent metal transporter-1 (DMT-1) contributes to maintaining cellular Mn 2؉ homeostasis and has recently been implicated in Fe 2؉ -mediated neurodegeneration in PD. In this study we describe a novel model for manganism that incorporates the genetically tractable nematode Caenorhabditis elegans. We show that a brief exposure to Mn 2؉ increases reactive oxygen species and glutathione production, decreases oxygen consumption and head mitochondria membrane potential, and confers DA neuronal death. DA neurodegeneration is partially dependent on a putative homologue to DMT-1, SMF-1, as genetic knockdown or deletion partially inhibits the neuronal death. Mn 2؉ also amplifies the DA neurotoxicity of the PD-associated protein ␣-synuclein. Furthermore, both SMF-1 and SMF-2 are expressed in DA neurons and contribute to PD-associated neurotoxicant-induced DA neuron death. These studies describe a C. elegans model for manganism and show that DMT-1 homologues contribute to Mn 2؉ -and PD-associated DA neuron vulnerability.Manganese is the second most prevalent transition metal and is an essential trace element that is necessary for normal growth and development. The heavy metal is required for a number of biological processes, including amino acid, lipid, and carbohydrate production, and metabolism, and is a cofactor for a diverse set of proteins, including arginases, transferases, hydrolases, ligases, and oxidoreductases (1, 2). Deficiencies in Mn 2ϩ , although rare, have been linked with bone malformation, hypertension, osteoporosis, and epilepsy (3, 4). Mn 2ϩ is also a potent neurotoxicant, and occupational exposure to high concentrations of the metal can result in a neurological condition called manganism (1, 5). Symptoms of manganism include tremors, bradykinesia, rigidity, and facial muscle spasms (1, 6, 7). Mn 2ϩ neurotoxicity has been associated with a number of occupational and environmental exposures. High incidence of manganism has been found in manganese miners and smelters (7-10). Welders appear to be particularly vulnerable to the disorder as manganese alloys used in the heating and joining of metals may result in the production and inhalation of manganese particles (11). Exposure to Mn 2ϩ -based pesticides, including maneb and mancozeb, has also been associated with the development of manganism (12)(13)(14). Furthermore, significant environmental exposures have been reported with water contamination and possibly with the manganese-containing anti-knock fuel additive methylcyclopentadienyl manganese tricarbonyl (12). Recently, high exposures to Mn 2ϩ have also been associated with psychoactive stimulant preparations for recreational drug use (15,16).Epidemiological studies suggest a significant correlation of exposure to high concent...

Caenorhabditis elegans: An Emerging Model System for Pesticide Neurotoxicity

“…Additionally, acute Mn exposure can lead to mitochondrial inhibition by disrupting mitochondrial membrane potential (Δψ) and oxygen consumption. Oxidative stress also resulted in the neurodegeneration of dopaminergic (DAergic) neurons, indicated by the fact that treated worms showed a significant decrease in DA concentration compared to untreated worms [143]. Similar neurodegeneration has been shown following exposure to mancozeb [144,145].…”

“…Manganese exposure by itself has been shown to result in a variety of detrimental effects in C. elegans [146][147][148]. One study demonstrates that even short exposures (30 min) to manganese result in production of ROS, as evidenced by a drastic increase in glutathione levels [143]. In this study, worms exposed to 50 mM of MnCl2 experienced a two-fold increase in the amount of ROS production.…”

“…Manganese-containing dithiocarbamate fungicides, such as maneb and mancozeb, have been researched heavily due to their neurotoxicity [143][144][145]. Manganese exposure by itself has been shown to result in a variety of detrimental effects in C. elegans [146][147][148].…”

Manganese Neurotoxicity

“…Mn exposure in worms has been associated with morphological alterations, reduced longevity, oxidative stress, and behavioral alterations, such as decreased head trash and body-bend frequencies Benedetto et al 2010;Settivari et al 2009;Wang and Xing 2008). Particularly, DAergic degenerations were observed after acute exposure to this metal (Benedetto et al 2010;Settivari et al 2009).…”

“…Particularly, DAergic degenerations were observed after acute exposure to this metal (Benedetto et al 2010;Settivari et al 2009). Benedetto et al, making use of various genetic strains of C. elegans in conjunction with the fluorescent-tagging of different classes of neuron types, have demonstrated that Mn causes a dose-dependent and specific degeneration of DAergic neurons (Benedetto et al 2010).…”