Fruitfly Model Of A Neuropathic Disease Demonstrates Novel Role For Proteins In The Family Of ATyr Pharma's Product Class

Main Category: Biology / Biochemistry
Article Date: 14 Jul 2009 - 1:00 PST

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Research published in the June 26, 2009 edition of Proceedings of National Academy of Sciences provides further evidence for novel roles of tRNA synthetases in disease, validating the therapeutic potential for aTyr Pharma's new class of naturally occurring protein agents. The aminoacyl tRNA synthetases are universal and essential components of protein synthesis machinery found in all organisms, but human synthetases have naturally occurring resected variants with potent cell signaling activities that are vital to normal functioning of humans. aTyr Pharma's proprietary product generating engine consists of these resected proteins (resectins) of human aminoacyl tRNA synthetases with cell signaling activities distinct from the protein synthesis activities. In this recently published study, a model of a human neuropathy was created in the fruit fly (Drosophila) by introducing mutations in the tyrosyl-tRNA synthetase which correspond to disease associated mutations in humans. These dominant mutations do not cause a loss in the protein synthesis activity, indicating that the neuropathy arises from distinct activities of this tRNA synthetase. This work provides further proof of noncanonical roles for tRNA synthetases in human disease.

The large team of scientists on the study included Professors Paul Schimmel and Xiang-Lei Yang, scientific co-founders of aTyr Pharma, and Leslie Nangle, Director of Research at aTyr Pharma, and was led by Albena Jordanova of the University of Antwerp. Other scientists contributing to this paper are from the University of Antwerp, Universiteit Leuven, and Florida Atlantic University. Professor Paul Schimmel of The Scripps Research Institute describes the significance of the work. "Charcot-Marie-Tooth (CMT) is one of the most common inherited neurological disorders, with typical symptoms usually emerging in early adulthood, including loss of muscle mass, pain and sensitivity, foot deformations and difficulties in walking. Human genome sequencing revealed that some CMT patients have mutations in a gene encoding tyrosyl-tRNA synthetase. While tRNA synthetases play an essential role in protein synthesis in all forms of life, these dominant mutations in CMT patients did not seem to manifest the disease through disruption of those protein synthesis activities. When the mutations found in humans are introduced into the Drosophila genome, the flies develop neurological defects that correspond to CMT in humans. While we are still trying to understand how mutations in the tRNA synthetase gene disrupt the neurological system of a complex organism, this study showed that there are neurological functions encoded in this gene."

According to Jeff Watkins, CEO of aTyr Pharma, "In the past few years, Professor Schimmel has discovered a whole new area of biology: novel signaling functions for naturally occurring proteins resected from ancient proteins such as tRNA synthetases. This work in Drosophila illustrates a surprising disease-causing role for tRNA synthetases that is not related to the well-studied protein synthesis activities of these enzymes. Instead, in humans and this fruit fly model, the tyrosyl-tRNA synthetase gene encodes a distinct function involved in the complex neurobiology of an organism. These novel activities are seen for other members of the tRNA synthetases family as well, and aTyr Pharma's portfolio capitalizes on this new area of biology by using these naturally occurring resectins with novel signaling activities to treat a wide variety of diseases, such as inflammation, automimmune, hematopoietic and metabolic disorders."

Source: aTyr Pharma