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<p>Several lines of evidence point to defects in the dolichol pathway as a major contributor to the development of Alzheimer’s disease and inflammation associated with the unfolded protein response. In particular, zinc deficiency impairs formation of dolichol phosphate and low levels of pyridine nucleotides (NAD or NADPH), due to niacin deficiency, result in reduced conversion of polyprenol to dolichol phosphate, leading to reduced <i>N</i>-glycosylation of proteins. The magnesium-dependent transfer of <i>N</i>-acetyl-<span>d</span>-glucosamine-1-phosphate between dolichol phosphate (necessary for <i>N</i>-glycosylation) and UMP (required for <i>O</i>-glycosylation) by DPAGT1 ties dolichol phosphate biosynthesis to the balance between <i>O</i>- and <i>N</i>-glycosylation. Alteration of protein glycosylation would affect the folding, function, and physical properties (e.g., solubility) of many glycoproteins, such as UDP-glucuronosyltransferase (anosmia), amyloid precursor protein, tau, acetylcholine receptors, ligand-gated ion channels, voltage-gated ion channels, and G protein-coupled receptors. Three of the five best documented stress-induced nutritional deficiencies (i.e., zinc, niacin, and magnesium) would contribute to alterations in glycosylation of these and many other proteins involved in the progression of Alzheimer’s disease.</p>

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Is dolichol pathway dysfunction a significant factor in Alzheimer’s disease?

  • 期刊论文

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  • 发表日期：

    2025年7月25日

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  • John V. Schloss

摘要

Several lines of evidence point to defects in the dolichol pathway as a major contributor to the development of Alzheimer’s disease and inflammation associated with the unfolded protein response. In particular, zinc deficiency impairs formation of dolichol phosphate and low levels of pyridine nucleotides (NAD or NADPH), due to niacin deficiency, result in reduced conversion of polyprenol to dolichol phosphate, leading to reduced N-glycosylation of proteins. The magnesium-dependent transfer of N-acetyl-d-glucosamine-1-phosphate between dolichol phosphate (necessary for N-glycosylation) and UMP (required for O-glycosylation) by DPAGT1 ties dolichol phosphate biosynthesis to the balance between O- and N-glycosylation. Alteration of protein glycosylation would affect the folding, function, and physical properties (e.g., solubility) of many glycoproteins, such as UDP-glucuronosyltransferase (anosmia), amyloid precursor protein, tau, acetylcholine receptors, ligand-gated ion channels, voltage-gated ion channels, and G protein-coupled receptors. Three of the five best documented stress-induced nutritional deficiencies (i.e., zinc, niacin, and magnesium) would contribute to alterations in glycosylation of these and many other proteins involved in the progression of Alzheimer’s disease.