New findings in promising mouse model for NGLY1

By Quirine Eijkenboom

This week one of our grantees, Dr. Tadashi Suzuki, and his team at RIKEN published an exciting new paper with some novel and unexpected findings about NGLY1. The results highlight the value of basic research and also provide some helpful information on new potential targets for treatment.

In the past, the RIKEN research team had already shown that when NGLY1 is absent, sugars normally removed from glycoproteins were subsequently improperly removed by another enzyme called ENGase. Their new studies proved that a complete knockout of the NGLY1 gene in mice (both copies of the gene are defective) led to death in mice model organisms before birth.  However, this could be rescued by a second knockout of the ENGase gene (http://bit.ly/EnPm17).

As a result of this double knockout, the mice survived, but they exhibited similar defects and symptoms to NGLY1 children: bent spines, trembling, limb clasping and shaking. Moreover, by 45 weeks, the survival rate of the mice was reduced to 60%. The fact that these mice models were showing similar symptoms to NGLY1 children allows them to be useful for testing potential therapies.

Dr. Suzuki stated that this research gave them new insights on how ENGase was involved in the NGLY1 pathway: "We thought that ENGase acted further downstream to NGLY1. We were surprised when the double knockout was able to suppress the lethality of NGLY1 mice. This was truly a case of serendipity".

These new findings thus suggest that preventing ENGase's action could alleviate symptoms of NGLY1 deficiency in mice. The next step would thus be to isolate an in-vivo (performed within an organism) inhibitor for ENGase and determine whether it actually mitigates the symptoms.

These findings present a potential therapeutic path to treating NGLY1 Deficiency and may be helpful to better understand other diseases as well. Thank you to our donors, especially Hiroshi Mikitani, who made this research possible.