Microglial Sp1 induced LRRK2 upregulation in response to manganese exposure, and 17ß-estradiol afforded protection against this manganese toxicity.
Neurotoxicology
; 103: 105-114, 2024 Jul.
Article
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| MEDLINE
| ID: mdl-38857675
ABSTRACT
Chronic exposure to elevated levels of manganese (Mn) causes a neurological disorder referred to as manganism, presenting symptoms similar to those of Parkinson's disease (PD), yet the mechanisms by which Mn induces its neurotoxicity are not completely understood. 17ß-estradiol (E2) affords neuroprotection against Mn toxicity in various neural cell types including microglia. Our previous studies have shown that leucine-rich repeat kinase 2 (LRRK2) mediates Mn-induced inflammatory toxicity in microglia. The LRRK2 promoter sequences contain three putative binding sites of the transcription factor (TF), specificity protein 1 (Sp1), which increases LRRK2 promoter activity. In the present study, we tested if the Sp1-LRRK2 pathway plays a role in both Mn toxicity and the protection afforded by E2 against Mn toxicity in BV2 microglial cells. The results showed that Mn induced cytotoxicity, oxidative stress, and tumor necrosis factor-α production, which were attenuated by an LRRK2 inhibitor, GSK2578215A. The overexpression of Sp1 increased LRRK2 promoter activity, mRNA and protein levels, while inhibition of Sp1 with its pharmacological inhibitor, mithramycin A, attenuated the Mn-induced increases in LRRK2 expression. Furthermore, E2 attenuated the Mn-induced Sp1 expression by decreasing the expression of Sp1 via the promotion of the ubiquitin-dependent degradation pathway, which was accompanied by increased protein levels of RING finger protein 4, the E3-ligase of Sp1, Sp1 ubiquitination, and SUMOylation. Taken together, our novel findings suggest that Sp1 serves as a critical TF in Mn-induced LRRK2 expression as well as in the protection afforded by E2 against Mn toxicity through reduction of LRRK2 expression in microglia.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Regulación hacia Arriba
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Factor de Transcripción Sp1
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Microglía
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Estradiol
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Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina
Límite:
Animals
Idioma:
En
Revista:
Neurotoxicology
Año:
2024
Tipo del documento:
Article