Title: Astrocyte-specific deletion of the transcription factor Yin Yang 1 in murine substantia nigra mitigates manganese-induced dopaminergic neurotoxicity.
Authors: Pajarillo, Edward; Johnson Jr, James; Rizor, Asha; Nyarko-Danquah, Ivan; Adinew, Getinet; Bornhorst, Julia; Stiboller, Michael; Schwerdtle, Tania; Son, Deok-Soo; Aschner, Michael; Lee, Eunsook
Published In J Biol Chem, (2020 11 13)
Abstract: Manganese (Mn)-induced neurotoxicity resembles Parkinson's disease (PD), but the mechanisms underpinning its effects remain unknown. Mn dysregulates astrocytic glutamate transporters, GLT-1 and GLAST, and dopaminergic function, including tyrosine hydroxylase (TH). Our previous in vitro studies have shown that Mn repressed GLAST and GLT-1 via activation of transcription factor Yin Yang 1 (YY1). Here, we investigated if in vivo astrocytic YY1 deletion mitigates Mn-induced dopaminergic neurotoxicity, attenuating Mn-induced reduction in GLAST/GLT-1 expression in murine substantia nigra (SN). AAV5-GFAP-Cre-GFP particles were infused into the SN of 8-week-old YY1 flox/flox mice to generate a region-specific astrocytic YY1 conditional knockout (cKO) mouse model. 3 weeks after adeno-associated viral (AAV) infusion, mice were exposed to 330 μg of Mn (MnCl2 30 mg/kg, intranasal instillation, daily) for 3 weeks. After Mn exposure, motor functions were determined in open-field and rotarod tests, followed by Western blotting, quantitative PCR, and immunohistochemistry to assess YY1, TH, GLAST, and GLT-1 levels. Infusion of AAV5-GFAP-Cre-GFP vectors into the SN resulted in region-specific astrocytic YY1 deletion and attenuation of Mn-induced impairment of motor functions, reduction of TH-expressing cells in SN, and TH mRNA/protein levels in midbrain/striatum. Astrocytic YY1 deletion also attenuated the Mn-induced decrease in GLAST/GLT-1 mRNA/protein levels in midbrain. Moreover, YY1 deletion abrogated its interaction with histone deacetylases in astrocytes. These results indicate that astrocytic YY1 plays a critical role in Mn-induced neurotoxicity in vivo, at least in part, by reducing astrocytic GLAST/GLT-1. Thus, YY1 might be a potential target for treatment of Mn toxicity and other neurological disorders associated with dysregulation of GLAST/GLT-1.
PubMed ID: 32893191
MeSH Terms: Animals; Astrocytes/cytology; Astrocytes/metabolism; Chlorides/toxicity; Down-Regulation/drug effects; Excitatory Amino Acid Transporter 1/genetics; Excitatory Amino Acid Transporter 1/metabolism; Excitatory Amino Acid Transporter 2/genetics; Excitatory Amino Acid Transporter 2/metabolism; Female; Histone Deacetylases/metabolism; Locomotion/drug effects; Male; Manganese Compounds; Manganese Poisoning/metabolism; Manganese Poisoning/pathology*; Mice; Mice, Knockout; RNA, Messenger/metabolism; Substantia Nigra/metabolism*; Tyrosine 3-Monooxygenase/genetics; Tyrosine 3-Monooxygenase/metabolism; YY1 Transcription Factor/genetics; YY1 Transcription Factor/metabolism*