Recently, a grassroots 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 Japan implicates the enzyme ENGase as the factor responsible for deficient protein degradation that occurs in the absence of mouse Ngly1 gene expression. Published in Proceedings of the National Academy of Science, the paper details how lack of the Ngly1 peptide 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 cytostol are instead aggregated in the cells.
(Left) In normal cells, misfolded proteins are deglycosylated predominantly by Ngly1 and are degraded efficiently. (Right) In the absence of Ngly1, ENGase acts on some portion of unfolded glycoproteins, which leaves a portion of the N-glycan. These proteins aggregate and could somehow be detrimental to the cells.