Drug target found for rare genetic disorder

A mouse study led by researchers from the RIKEN–Max Planck Joint Research Center for Systems Chemical Biology has revealed a potential drug target for a newly identified human genetic disease known as NGLY1 deficiency¹. “This is a major breakthrough for patients and their families,” says the research leader, Tadashi Suzuki.

NGLY1 deficiency is an extremely rare genetic disorder characterized by neurological dysfunctions, abnormal tear production and liver disease. Scientists in the United States discovered the first known case of NGLY1 deficiency in 2012. Since then, more than 20 additional cases have been documented worldwide. All these people share mutations in the NGLY1 gene, which codes for an enzyme that plays a critical role in recycling cellular waste. This enzyme, N-glycanase, removes sugar molecules—called glycans—from misfolded proteins, which allows the proteins to be subsequently broken down and recycled.

Suzuki first identified N-glycanase in mammalian cells more than 20 years ago. Since then, he and scientists around the world have revealed various aspects of the enzyme’s functional importance. However, it remained unclear what role N-glycanase played in the ‘quality-control’ machinery for unwanted proteins, and hence its function in NGLY1 deficiency disorder. To investigate, Suzuki and his colleagues studied mouse embryonic fibroblasts that had been genetically engineered to lack the NGLY1 gene.

In these cells, the researchers observed that the proteins still lost their sugar chains, even in the absence of the N-glycanase enzyme, but the sugars stuck around, creating aggregates of undesired protein junk (Fig. 1).

Suzuki suspected that another enzyme might be involved in the de-sugaring process. Endo-β-N-acetylglucosaminidase (ENGase) normally degrades the free sugars left behind after cleavage by N-glycanase, and was not thought to act directly on misfolded proteins. Surprisingly, however, the team found that in mouse cells without N-glycanase activity, ENGase was partially stripping sugars directly off the proteins. The ENGase attack left one key sugar molecule attached to the protein, which explained why the proteins could not be fully degraded.

Interestingly, Suzuki’s team observed normal protein destruction in mouse cells engineered to lack both N-glycanase and ENGase. “This was contrary to our expectation, as it is generally believed that glycans have to be removed from glycoproteins prior to this proteasomal degradation,” says Suzuki. Although counterintuitive, the result suggests that inhibiting ENGase with a drug could help overcome the problems associated with NGLY1 deficiency. “We are currently working together with chemists to design inhibitors that could work in patients,” Suzuki says.