Manganese (Mn) is a potent neurotoxin. We hypothesize that PARK2, a strong Parkinson's disease (PD) genetic risk factor, alters neuronal vulnerability to modifiers of cellular Mn status, particularly at the level of mitochondrial dysfunction and oxidative stress. The long-term goal of this research is to elucidate the basis of Mn-induced neurotoxicity and to identify mechanistic-based neuroprotective strategies to mitigate human Mn exposure risk. Our approach will utilize a novel high-throughput assay of intracellular Mn levels to identify small molecule modifiers of cellular Mn status and neurotoxicity. Genetic modifiers of Mn transport and toxicity will be defined and translational studies of existing and newly identified genetic and small molecule modifiers of Mn toxicity will be performed utilizing a primary human neuronal model system based upon human induced pluripotent stem cell (hiPSC) technology.
Aim 1 will identify lead compounds that alter neuronal Mn transport and toxicity in vitro using striatal and mesencephalic murine neuronal cell lines and in vivo using C. elegans.
Aim 2 will delineate functional pathways that regulate Mn transport and toxicity in vivo and in vitro.
Specific Aim 3 will test the hypothesis that human neuronal models of PD exhibit increased sensitivity to perturbations of cellular Mn status.
These specific aims hold the promise of delineating common initiator signals for the modulation of Mn neurotoxicity, shedding light on mechanisms and susceptibility associated with exposure to this metal. This dual-PI proposal is bolstered by its use of innovative state-of-the-art complimentary approaches in diverse model systems.
The proposed studies will (1) provide novel and innovative information on functional and hierarchal relationships between small molecule modifiers of cellular manganese (Mn) status and Mn neurotoxicity, (2) identify novel therapeutic modalities for Mn-induced neurotoxicity, and (3) delineate gene-environment interactions within and across species in the integrated systems response to Mn. Our multidisciplinary approach seeks to define the functional domains that regulate key nodes of interaction between Mn and biological systems and the role genetic traits of susceptibility play in mediating molecular mechanisms of neurological disease influence by Mn exposure.
|Nguyen, Thuy T; Caito, Samuel W; Zackert, William E et al. (2016) Scavengers of reactive Î³-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7. Aging (Albany NY) 8:1759-80|
|Claassen, Daniel O; Dobolyi, David G; Isaacs, David A et al. (2016) Linear and Curvilinear Trajectories of Cortical Loss with Advancing Age and Disease Duration in Parkinson's Disease. Aging Dis 7:220-9|
|Henze, Andrea; Homann, Thomas; Rohn, Isabelle et al. (2016) Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin. Sci Rep 6:37346|
|Peres, Tanara V; Schettinger, Maria Rosa C; Chen, Pan et al. (2016) "Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies". BMC Pharmacol Toxicol 17:57|
|Reckziegel, PatrÃcia; Chen, Pan; Caito, Sam et al. (2016) Extracellular dopamine and alterations on dopamine transporter are related to reserpine toxicity in Caenorhabditis elegans. Arch Toxicol 90:633-45|
|Kwakye, Gunnar F; McMinimy, Rachael A; Aschner, Michael (2016) Disease-Toxicant Interactions in Parkinson's Disease Neuropathology. Neurochem Res :|
|Tidball, Andrew M; Neely, M Diana; Chamberlin, Reed et al. (2016) Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells. PLoS One 11:e0150372|
|Zhang, Ziyan; Singh, Rajat; Aschner, Michael (2016) Methods for the Detection of Autophagy in Mammalian Cells. Curr Protoc Toxicol 69:20.12.1-20.12.26|
|Song, Han; Zheng, Gang; Liu, Yang et al. (2016) Cellular uptake of lead in the blood-cerebrospinal fluid barrier: Novel roles of Connexin 43 hemichannel and its down-regulations via Erk phosphorylation. Toxicol Appl Pharmacol 297:1-11|
|Yuntao, Fang; Chenjia, Guo; Panpan, Zhang et al. (2016) Role of autophagy in methylmercury-induced neurotoxicity in rat primary astrocytes. Arch Toxicol 90:333-45|
Showing the most recent 10 out of 161 publications