MGST3 regulates BACE1 protein translation and amyloidogenesis by controlling the RGS4-mediated AKT signaling pathway

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Microsomal glutathione transferase 3 (MGST3) influences eicosanoid and glutathione metabolism, processes linked to oxidative stress and apoptosis.
• These metabolic roles suggest a potential involvement of MGST3 in Alzheimer's disease pathophysiology.

Purpose of the Study:

• To investigate the role of MGST3 in regulating beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloidogenesis.
• To elucidate the molecular mechanisms by which MGST3 affects BACE1 expression and amyloid production.

Main Methods:

• MGST3 knockdown in cell lines.
• Analysis of BACE1 protein levels, amyloidogenesis, and apoptosis indicators.
• RNA-sequencing (RNA-seq) to identify target genes.
• Silencing of Regulator of G-protein signaling 4 (RGS4).
• Investigation of AKT signaling pathway activity.

Main Results:

• MGST3 knockdown reduced BACE1 protein levels and amyloidogenesis without altering reactive oxygen species.
• MGST3 knockdown selectively reduced apoptosis indicators and was independent of cysteinyl leukotrienes.
• RNA-seq identified RGS4 as a MGST3 target gene; RGS4 silencing inhibited BACE1 translation.
• MGST3 and RGS4 regulated BACE1 via the AKT signaling pathway, evidenced by reduced phosphorylated AKT levels.

Conclusions:

• MGST3 plays a critical role in regulating amyloidogenesis by controlling BACE1 protein expression.
• The mechanism involves RGS4 and downstream AKT signaling.
• MGST3 represents a potential therapeutic target for Alzheimer's disease.