Upregulation of NFE2L1 reduces ROS levels and α-synuclein aggregation caused by GBA1 knockdown.

Autor: Li Y; Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China., Wen S; Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China., Xiang W; Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China., Shen F; Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China., Jiang N; Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China., Zhang J; Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: jinzhang@fudan.edu.cn., Ma D; Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Children's Hospital, Fudan University, Shanghai, 201102, China. Electronic address: duanma@fudan.edu.cn.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Nov 19; Vol. 734, pp. 150640. Date of Electronic Publication: 2024 Sep 02.
DOI: 10.1016/j.bbrc.2024.150640
Abstrakt: Biallelic mutations in the GBA1 gene result in Gaucher disease (GD), and both patients with GD and carriers of a single GBA1 mutation have an increased susceptibility to Parkinson's disease (PD), but the underlying mechanisms of this association are not yet clear. In previous studies, we established Gba1 F213I point mutation mice and found that homozygous Gba1 F213I mutant mice died shortly after birth, while heterozygous mice could survive normally. In this study, we investigated the transcriptomic changes in the brain tissue of Gba1 F213I heterozygous mice, identifying 138 differentially expressed genes. Among them, Nfe2l1 was the most significantly downregulated gene. Inhibition or knockdown of GBA1 in BE(2)-M17 cells resulted in decreased expression levels of NFE2L1. Knockdown of GBA1 or NFE2L1 could lead to an elevation in intracellular aggregation of α-synuclein (α-syn) and reactive oxygen species (ROS) levels, while upregulation of NFE2L1 effectively mitigated those cellular manifestations induced by GBA1 knockdown. In summary, our in vitro results showed that upregulation of NFE2L1 may provide a therapeutic benefit for cellular phenotypes resulting from GBA1 knockdown, providing new insights for future research on GD and GBA1-associated PD.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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