The lithium-magnesium-zinc axis under stress: regulation of N-glycosylation-linked proteostasis and Alzheimer's...

Inflammation resulting from the unfolded protein response to glycosylation dysfunction may be the key driver in the progression of Alzheimer's disease. Stress increases the risk of Alzheimer's disease, in part, by depleting essential cofactors required by enzymes involved in N-glycosylation (the first and third, second, fourth, and fifth enzymes-essential cofactors required for dolichol diphosphate-sugar conjugate synthesis are, respectively: DHRSX-NAD/NADPH, SRD5A3-NADPH, DOLK-Zn²⁺, and DPAGT1-Mg²⁺). Lithium reduces the risk of Alzheimer's disease by: (1) increasing transcription of DPAGT1, the gene for the first committed enzyme of N-glycosylation, stimulating levels of β-catenin through glycogen synthase kinase 3-β (GSK-3β) inhibition; (2) increasing transcription of SRD5A3, DHRSX, and DOLK, the genes for the enzymes of dolichol phosphate synthesis, stimulating levels of transcription factors through GSK-3β inhibition; and (3) inositol monophosphatase (IMPase) inhibition-increased autophagy clearance of amyloid produced by N-glycosylation pathway dysfunction. Together, lithium, magnesium, and zinc constitute a regulatory axis for protein N-glycosylation, in which lithium levels determine the threshold for pathology during magnesium and zinc depletion under stress. Magnesium is also required by the oligosaccharyltransferase complex, which catalyzes the conversion of dolichol-pyrophosphate-GlcNAc₂-Mana₉-Glc₃ and a protein asparaginyl residue to an N-glycosylated protein and dolichol-pyrophosphate. Stress-induced Mg²⁺ deficiency impairs the oligosaccharyltransferase complex by affecting MAGT1 (magnesium transporter 1) and the STT3A component, resulting in N-glycan defects and hypoglycosylation. Endoplasmic reticulum stress, resulting from the unfolded protein response, stimulates N-glycan branching (bisected N-glycans) and hyperglycosylation due to the effect on TUSC3 (a regulator of Mg²⁺ influx) and the STT3B component of the oligosaccharyltransferase complex.