Chronic exposure to high concentrations of manganese (Mn) results in adverse neurological health effects commonly referred to as manganism. Manganese neurotoxicity is a significant toxicological problem resulting from the use of manganese as a gasoline additive, and in welding, metal industries, pesticide manufacturing, pharmaceutical preparations, infant food formulations, and battery production. Manganese predominantly accumulates in the basal ganglia structures and causes mitochondrial dysfunction, oxidative stress, and apoptosis. However, cellular and molecular mechanisms underlying manganese neurotoxicity are poorly understood. We have been studying mitochondrial-dependent apoptotic signaling in manganese neurotoxicity and found that protein kinase C-delta (PKCd), a member of the novel PKC isoform family, is persistently activated by caspase-3 to promote apoptosis during manganese exposure. While studying the apoptotic signaling pathway in cell culture models of manganese neurotoxicity, we also unexpectedly identified that PKCd is upregulated both in protein and mRNA levels during manganese treatment. Further analysis of the PKCd promoter revealed that two key transcription factors, NFkB and SP1, regulate PKCd gene expression. Thus, our competitive renewal proposal aims to systematically characterize this gene-environment interaction by studying novel molecular mechanisms underlying manganese-induced upregulation of the proapoptotic PKCd gene. We propose to complete the study by pursuing the following specific aims: i) To characterize upregulation of an oxidative stress-sensitive proapoptotic kinase PKCd in mouse primary neuronal cultures and animal models following manganese exposure, ii) To investigate molecular mechanisms of manganese-induced upregulation of PKCd by examining its transcriptional regulation of a PKCd promoter, and iii) To further define the functional role of NFkB and SP1-dependent PKCd upregulation in manganese-induced neuronal damage during chronic manganese exposure. Cellular, molecular, and neurochemical approaches in relevant cell cultures and animal models of manganese neurotoxicity will be used. We anticipate that the proposed study will provide comprehensive information about how environmental exposure to manganese can alter the expression of the key proapoptotic gene PKCd to augment manganese neurotoxicity, and this knowledge may advance the development of novel translational approaches for the treatment of manganese neurotoxicity.
Environmental exposure to excessive manganese impairs basal ganglia function, resulting in a neurological disorder relatively similar to Parkinsonism commonly known as Manganism. Manganese exposure is of serious concern due to the increased incidences of extrapyramidal neurological symptoms among miners and industrial workers, including welders. Manganese predominantly accumulates in the basal ganglia structures and causes mitochondrial dysfunction, oxidative stress, and apoptosis. However, cellular and molecular mechanisms underlying manganese neurotoxicity are poorly understood. The proposed study will elucidate the neurotoxic mechanisms underlying manganese induced upregulation of a proapoptotic kinase PKCd and its functional relevance to manganese neurotoxicity.
|Asaithambi, Arunkumar; Ay, Muhammet; Jin, Huajun et al. (2014) Protein kinase D1 (PKD1) phosphorylation promotes dopaminergic neuronal survival during 6-OHDA-induced oxidative stress. PLoS One 9:e96947|
|Harischandra, Dilshan S; Kondru, Naveen; Martin, Dustin P et al. (2014) Role of proteolytic activation of protein kinase C? in the pathogenesis of prion disease. Prion 8:143-53|
|Jin, Huajun; Kanthasamy, Arthi; Anantharam, Vellareddy et al. (2011) Transcriptional regulation of pro-apoptotic protein kinase Cdelta: implications for oxidative stress-induced neuronal cell death. J Biol Chem 286:19840-59|
|Latchoumycandane, Calivarathan; Anantharam, Vellareddy; Jin, Huajun et al. (2011) Dopaminergic neurotoxicant 6-OHDA induces oxidative damage through proteolytic activation of PKC? in cell culture and animal models of Parkinson's disease. Toxicol Appl Pharmacol 256:314-23|
|Zhang, Danhui; Kanthasamy, Arthi; Anantharam, Vellareddy et al. (2011) Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line. Toxicol Appl Pharmacol 254:65-71|
|Song, C; Kanthasamy, A; Jin, H et al. (2011) Paraquat induces epigenetic changes by promoting histone acetylation in cell culture models of dopaminergic degeneration. Neurotoxicology 32:586-95|
|Martin, Dustin P; Anantharam, Vellareddy; Jin, Huajun et al. (2011) Infectious prion protein alters manganese transport and neurotoxicity in a cell culture model of prion disease. Neurotoxicology 32:554-62|
|Saminathan, Hariharan; Asaithambi, Arunkumar; Anantharam, Vellareddy et al. (2011) Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote PKCýý-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model. Neurotoxicology 32:567-77|
|Afeseh Ngwa, Hilary; Kanthasamy, Arthi; Gu, Yan et al. (2011) Manganese nanoparticle activates mitochondrial dependent apoptotic signaling and autophagy in dopaminergic neuronal cells. Toxicol Appl Pharmacol 256:227-40|
|Sun, Faneng; Kanthasamy, Anumantha G; Kanthasamy, Arthi (2011) Measurement of proteasomal dysfunction in cell models of dopaminergic degeneration. Methods Mol Biol 758:293-305|
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