Parkinson's disease (PD) is a neurodegenerative disease which can be ascribed in only 10-20% of cases to genetics. Epidemiological evidence suggests that PD is more common in rural areas, where its increased prevalence is associated with the use of pesticides, herbicides and heavy metals, including manganese (Mn). Chronic exposure to high Mn levels causes manganism, which has multiple shared features with PD, but the mechanisms by which Mn induces neurotoxicity have yet to be fully established. Mn decreases expression of glutamate transporter GLT-1, which regulates synaptic glutamate levels and prevents excitotoxic neuronal injury. Our preliminary studies indicate that the transcription factor yin yang 1 (YY1) plays a critical role in the effect of Mn on GLT-1. Accordingly, delineating the precise mechanism of Mn-induced dysregulation of GLT-1 expression is critical in advancing our understanding of Mn neurotoxicity. Moreover, identifying molecular targets of Mn-induced GLT-1 dysfunction will have broad applicability, since a plethora of neurodegenerative diseases, such as PD, Alzheimer's disease and amyotrophic lateral sclerosis are associated with perturbed glutamate homeostasis secondary to GLT-1 dysfunction. Thus, our long-term goal is to understand the mechanisms involved in the regulation of GLT-1 expression in relation to the excitotoxic neurodegeneration. Our immediate objective is to determine how YY1 regulates Mn-induced repression of GLT-1. Here, we present preliminary data characterizing a previously unknown role of YY1 in Mn-induced repression of GLT-1. Among our findings, we determined that Mn increases YY1 expression via NF-?B. In addition, epigenetic modifier histone deacetylases (HDACs) serve as co-repressors of YY1, and HDAC inhibitors (HDACi) reverse Mn-induced repression of GLT-1 promoter activity. Given these observations, we hypothesize that Mn-induced GLT-1 repression by NF-?B-dependent YY1 activation, with HDACs acting as co-repressors, mediates Mn-induced neurotoxicity. Our proposed work is the first in the field to explore the effect of Mn on GLT-1 expression via YY1 at the transcriptional level. Our hypothesis will be tested in the following specific aims: 1) Determine if astrocytic YY1 mediates Mn-induced neurotoxicity by impairing GLT-1 expression and function using astrocyte-specific YY1 conditional knockout mice, 2) Delineate the molecular mechanisms of Mn-induced activation of YY1 and its role in regulating GLT-1 function in vitro using primary astrocytes, and 3) Test if Mn- enhanced YY1 expression and the ensuing GLT-1 repression are regulated by HDAC epigenetic modification. Our studies will provide novel insights into the mechanism(s) underlying the role of the YY1 pathway in Mn-induced repression of GLT-1 function and Mn-induced neurotoxicity. Moreover, the outcome of this study will offer novel therapeutic strategies for neurodegenerative diseases associated with impairment in GLT-1 function and excitotoxicity.

Public Health Relevance

Chronic exposure to the elevated levels of manganese (Mn) causes a reduction of astrocytic glutamate transporter GLT-1 expression, which is also observed in a plethora of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. The mechanism of this Mn effect on GLT-1 expression is not well understood, but delineating the molecular mechanism involved is critical in advancing Mn neurotoxicity studies as well as developing strategies of therapeutics for neurodegenerative diseases associated with dysfunction of GLT-1. Therefore, in this proposal, we will study the mechanism involved in Mn-induced repression of GLT-1 at the transcriptional level to identify the molecular target of Mn effect on GLT-1 by testing the role of the transcriptin factor yin yang 1 (YY1) in this Mn effect.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hollander, Jonathan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Florida Agricultural and Mechanical University
Schools of Pharmacy
United States
Zip Code
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
Ignacio, Rosa Mistica C; Lee, Eun-Sook; Wilson, Andrew J et al. (2018) Chemokine Network and Overall Survival in TP53 Wild-Type and Mutant Ovarian Cancer. Immune Netw 18:e29
Ignacio, Rosa Mistica C; Gibbs, Carla R; Lee, Eun-Sook et al. (2018) The TGF?-EGFR-Akt signaling axis plays a role in enhancing proinflammatory chemokines in triple-negative breast cancer cells. Oncotarget 9:29286-29303
Ignacio, Rosa Mistica C; Dong, Yuan-Lin; Kabir, Syeda M et al. (2018) CXCR2 is a negative regulator of p21 in p53-dependent and independent manner via Akt-mediated Mdm2 in ovarian cancer. Oncotarget 9:9751-9765
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
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
Lee, Eunsook; Karki, Pratap; Johnson Jr, James et al. (2017) Manganese Control of Glutamate Transporters' Gene Expression. Adv Neurobiol 16:1-12
Choi, Hyeongjwa; Ignacio, Rosa Mistica C; Lee, Eun-Sook et al. (2017) Augmented Serum Amyloid A1/2 Mediated by TNF-induced NF-?B in Human Serous Ovarian Epithelial Tumors. Immune Netw 17:121-127
Karki, Pratap; Johnson Jr, James; Son, Deok-Soo et al. (2017) Transcriptional Regulation of Human Transforming Growth Factor-? in Astrocytes. Mol Neurobiol 54:964-976
Choi, Hyeongjwa; Ignacio, Rosa Mistica C; Lee, Eun-Sook et al. (2017) Localization of Serum Amyloid A3 in the Mouse Ovary. Immune Netw 17:261-268

Showing the most recent 10 out of 13 publications