SMF-1, SMF-2 and SMF-3 DMT1 Orthologues Regulate and Are Regulated Differentially by Manganese Levels in C. elegans (original) (raw)
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Journal of Biological Chemistry, 2009
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 alpha-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 disturbs metal and protein homeostasis in Caenorhabditis elegans
Parkinson's disease (PD) is a debilitating motor and cognitive neurodegenerative disorder for which there is no cure. While aging is the major risk factor for developing PD, clear environmental risks have also been identified. Environmental exposure to the manganese (Mn) metal is a prominent risk factor for developing PD and occupational exposure to high levels of Mn can cause a syndrome known as manganism, which has symptoms that closely resemble PD. In this study, we developed a model of manganism in the environmentally tractable nematode, Caenorhabditis elegans. We find that, in addition to previously described modes of Mn toxicity, which primarily include mitochondrial dysfunction and oxidative stress, Mn exposure also significantly antagonizes protein homeostasis, another key pathological feature associated with PD and many age-related neurodegenerative diseases. Mn treatment activates the ER unfolded protein response, severely exacerbates toxicity in a disease model of protein misfolding, and alters aggregate solubility. Further, aged animals, which have previously been shown to exhibit decreased protein homeostasis, are particularly susceptible to Mn toxicity when compared to young animals, indicating that the aging process sensitizes animals to metal toxicity. Mn exposure also significantly alters iron (Fe) and calcium (Ca) homeostasis, which is important for mitochondrial and ER health and which may further compound toxicity. These findings indicate that modeling manganism in C. elegans can provide a useful platform for identifying therapeutic interventions for ER stress, proteotoxicity, and age-dependent susceptibilities, key pathological features of PD and other related neurodegenerative diseases.
Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity
Neurotoxicity research, 2018
Excessive levels of the essential metal manganese (Mn) may cause a syndrome similar to Parkinson's disease. The model organism Caenorhabditis elegans mimics some of Mn effects in mammals, including dopaminergic neurodegeneration, oxidative stress, and increased levels of AKT. The evolutionarily conserved insulin/insulin-like growth factor-1 signaling pathway (IIS) modulates worm longevity, metabolism, and antioxidant responses by antagonizing the transcription factors DAF-16/FOXO and SKN-1/Nrf-2. AKT-1, AKT-2, and SGK-1 act upstream of these transcription factors. To study the role of these proteins in C. elegans response to Mn intoxication, wild-type N2 and loss-of-function mutants were exposed to Mn (2.5 to 100 mM) for 1 h at the L1 larval stage. Strains with loss-of-function in akt-1, akt-2, and sgk-1 had higher resistance to Mn compared to N2 in the survival test. All strains tested accumulated Mn similarly, as shown by ICP-MS. DAF-16 nuclear translocation was observed by fl...
DMT1: a mammalian transporter for multiple metals
Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine, 2003
DMT1 has four names, transports as many as eight metals, may have four or more isoforms and carries out its transport for multiple purposes. This review is a start at sorting out these multiplicities. A G185R mutation results in diminished gastrointestinal iron uptake and decreased endosomal iron exit in microcytic mice and Belgrade rats. Comparison of mutant to normal rodents is one analytical tool. Ectopic expression is another. Antibodies that distinguish the isoforms are also useful. Two mRNA isoforms differ in the 3' UTR: +IRE DMT1 has an IRE (Iron Responsive Element) but -IRE DMT1 lacks this feature. The +/-IRE proteins differ in the distal 18 or 25 amino acid residues after shared identity for the proximal 543 residues. A major function is serving as the apical iron transporter in the lumen of the gut. The +IRE isoform appears to have that role. Another role is endosomal exit of iron. Some evidence indicts the -IRE isoform for this function. In our ectopic expression assa...