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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Biallelic mutations in the GBA1 gene cause Gaucher disease (GD).
• GD patients and GBA1 mutation carriers have increased Parkinson's disease (PD) susceptibility, but mechanisms are unclear.
• Previous work established Gba1 F213I point mutation mice, with heterozygous mice surviving normally.

Purpose of the Study:

• Investigate transcriptomic changes in Gba1 F213I heterozygous mouse brain tissue.
• Determine the role of Nfe2l1 in GBA1-associated cellular phenotypes.
• Explore NFE2L1 as a potential therapeutic target for GBA1-related PD.

Main Methods:

• Transcriptomic analysis of Gba1 F213I heterozygous mouse brain tissue.
• GBA1 inhibition/knockdown in BE(2)-M17 cells.
• NFE2L1 knockdown and upregulation experiments.
• Assessment of alpha-synuclein aggregation and reactive oxygen species (ROS) levels.

Main Results:

• Identified 138 differentially expressed genes in mouse brain tissue, with Nfe2l1 being significantly downregulated.
• GBA1 inhibition/knockdown decreased NFE2L1 expression in cells.
• GBA1 or NFE2L1 knockdown increased alpha-synuclein aggregation and ROS levels.
• NFE2L1 upregulation mitigated cellular phenotypes caused by GBA1 knockdown.

Conclusions:

• Nfe2l1 is downregulated in GBA1 deficiency and contributes to cellular pathologies.
• Upregulation of NFE2L1 shows therapeutic potential for GBA1 knockdown-induced cellular phenotypes.
• Findings offer new insights into GD and GBA1-associated PD pathogenesis and potential treatments.