Mn is an essential metal with neurotoxic properties in excess. Increasingly high exposure to manganese (Mn) in adults is associated with subclinical parkinsonian movements and postural instability, increased risk for Parkinson's disease (PD) or parkinsonism, and at the highest levels with manganism, a parkinsonian-like disorder, which is not ameliorated after cessation of exposure. Developmental and childhood Mn exposures have been associated with cognitive, behavioral as well as motor function alterations. Mn neurotoxicity involves both direct toxicity to neurons as well as neuroinflammatory responses. Here, we propose to continue our Mn neurotoxicity research program with a focus on the identification and mechanistic relationships of precise molecular targets of Mn neurotoxicity with exposures proximate to the transition from replete to neurotoxic levels of Mn ? environmentally relevant dosing. We hypothesize that threshold-level Mn neurotoxicity occurs via alteration of Mn-dependent/-activated biological functions. We will test the hypothesis as follows:
In Specific Aim 1 we will identify the mechanistic basis by which Mn alters insulin/insulin-like growth factor (IGF) related metabolic pathway signaling in neurons and the highly interconnected mTOR (mTORC1 and mTORC2), AKT and ATM/p53 metabolic signaling systems, both in worms and mammalian systems. Studies in Specific Aim 2 will refute or establish a mechanistic relationship between dopamine (DA) neurobiology and the insulin/IGF related signaling pathways in Mn neurotoxicity. Finally, in Specific Aim 3, we will define the mechanistic relationships of the insulin/IGF related signaling pathways and cellular Mn neurotoxicity outcomes. This highly interactive experimental design brings to bear innovative and complementary expertise to assess functional domains that regulate key nodes of interaction between Mn and biological systems, focusing on whether the threshold-level for Mn-induced neurotoxicity occurs via alteration of Mn-dependent/-activated biological functions. The studies are geared to address these timely objectives with translational extrapolation from the nematode to humans.
The proposed studies will (1) identify the mechanistic basis by which manganese (Mn) alters insulin/insulin-like growth factor (IGF) related signaling and the highly interconnected mTOR (mTORC1 and mTORC2), AKT and ATM/p53 metabolic signaling systems in neurons, (2) refute or establish a mechanistic relationship between dopamine (DA) neurobiology and the insulin/IGF related signaling pathways, and (3) define the mechanistic relationships of the insulin/IGF related signaling pathways and cellular Mn neurotoxicity outcomes. Our multidisciplinary approach seeks to define the functional domains that regulate key nodes of interaction between Mn and biological systems, and determine if the threshold-level for Mn-induced neurotoxicity occurs via alteration of Mn-dependent/-activated biological functions.
|Peres, Tanara V; Arantes, Leticia P; Miah, Mahfuzur R et al. (2018) Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity. Neurotox Res :|
|Chiou, Brian; Neal, Emma H; Bowman, Aaron B et al. (2018) Pharmaceutical iron formulations do not cross a model of the human blood-brain barrier. PLoS One 13:e0198775|
|Pajarillo, Edward; Johnson Jr, James; Kim, Judong et al. (2018) 17?-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity. Neurotoxicology 65:280-288|
|Meng, Qingtao; Wu, Shenshen; Wang, Yajie et al. (2018) MPO Promoter Polymorphism rs2333227 Enhances Malignant Phenotypes of Colorectal Cancer by Altering the Binding Affinity of AP-2?. Cancer Res 78:2760-2769|
|Karki, Pratap; Hong, Peter; Johnson Jr, James et al. (2018) Arundic Acid Increases Expression and Function of Astrocytic Glutamate Transporter EAAT1 Via the ERK, Akt, and NF-?B Pathways. Mol Neurobiol 55:5031-5046|
|Ke, Tao; Gonçalves, Filipe Marques; Gonçalves, Cinara Ludvig et al. (2018) Post-translational modifications in MeHg-induced neurotoxicity. Biochim Biophys Acta Mol Basis Dis :|
|Rohn, Isabelle; Marschall, Talke Anu; Kroepfl, Nina et al. (2018) Selenium species-dependent toxicity, bioavailability and metabolic transformations in Caenorhabditis elegans. Metallomics 10:818-827|
|Johnson Jr, James; Pajarillo, Edward Alain B; Taka, Equar et al. (2018) Valproate and sodium butyrate attenuate manganese-decreased locomotor activity and astrocytic glutamate transporters expression in mice. Neurotoxicology 64:230-239|
|Casjens, Swaantje; Dydak, Urike; Dharmadhikari, Shalmali et al. (2018) Association of exposure to manganese and iron with striatal and thalamic GABA and other neurometabolites - Neuroimaging results from the WELDOX II study. Neurotoxicology 64:60-67|
|Pinkas, Adi; Cunha Martins Jr, Airton; Aschner, Michael (2018) C. elegans-An Emerging Model to Study Metal-Induced RAGE-Related Pathologies. Int J Environ Res Public Health 15:|
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