Rare Genetic Disease May Adversely Affect Protein Glycosylation, Causing Pathogenic Protein Aggregation

Recently, a grass-roots effort initiated by families and clinicians led to the discovery of a human genetic disorder with severe consequences that is linked to a mutation in the human NGLY1 gene. In a big step towards understanding the effects of this mutation, research by scientists at the RIKEN-Max Planck Joint Research Center in Wako, Japan implicates the enzyme ENGase as the factor responsible for deficient protein degradation that occurs in the absence of mouse Ngly1 gene expression. Published online in PNAS, the report details how lack of the Ngly1 protein results in the incomplete removal of the sugar portion of glycoproteins—a process called deglycosylation. The result is that proteins that should be broken down in the cytosol are instead aggregated in the cells. The ability of proteins to function and interact properly with other molecules often depends on the protein’s three-dimensional configuration, which can be changed through the addition or subtraction of sugar chains. When proteins are not made correctly, they are sent to be broken down in the cytosol. NGLY1 is a cytosolic enzyme that removes the sugar chains from specific types of glycoproteins, and ENGase is another cytosolic enzyme in animal cells that degrades the free sugars left behind. The big question is whether NGLY1 deficiency affects protein degradation, and if so, how. The RIKEN-Max Planck researchers tackled this problem by first creating a model glycoprotein for examining this process in animal cells. Next, they expressed the model protein in cells derived from four types of mice (wild-type, Ngly1-knockout, Engase-knockout, and double-knockout) and measured how much of the model protein was degraded and how much of the undegraded portion still had attached sugar chains.
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