Presentation Title

CMT causing mutations increase stress granule formation

Faculty Mentor

Sarah Mitchell

Start Date

18-11-2017 12:30 PM

End Date

18-11-2017 1:30 PM

Location

BSC-Ursa Minor 87

Session

Poster 2

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

Charcot Marie Tooth Neuropathy (CMT) is the most common inherited neurodegenerative disease, affecting ~20 in 10,000 people. A major class of proteins mutated in CMT patients is tRNA synthetases, enzymes that charge tRNAs with amino acids. However, some mutations that cause CMT do not reduce the ability of tRNA synthetases to catalyze this reaction. Recently, several tRNA synthetases associated with CMT were found to have conserved mRNA binding activity. It is possible that CMT could be caused by malfunction of the mRNA regulation by these proteins.

One mode of mRNA regulation by proteins is the localization of mRNA to large, stress-induced assemblies of RNA and protein called stress granules. Interestingly, some tRNA synthetases are found in these assemblies and aberrant stress granule dynamics are associated with a variety of neurodegenerative diseases. These observations raise the exciting possibility that CMT associated mutations in tRNA synthetases alter stress granule dynamics, leading to disease. Indeed, we find that yeast strains carrying a CMT associated mutation in Hts1 (histidine tRNA synthetase), form a significantly higher number of stress granules under stress conditions associated with high growth density. We are currently studying additional Hts1 mutations, as well as CMT causing mutations in tyrosine tRNA synthetase (Tys1). These assays will provide insights into the mechanisms of mRNA regulation by tRNA synthetases, and potentially yield new information about the causes of CMT.

Summary of research results to be presented

We have identified one CMT causing mutation in histidine tRNA synthetase that causes an increase in stress granule formation. We are currently testing the effects of four additional CMT causing mutations on stress granule formation.

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Nov 18th, 12:30 PM Nov 18th, 1:30 PM

CMT causing mutations increase stress granule formation

BSC-Ursa Minor 87

Charcot Marie Tooth Neuropathy (CMT) is the most common inherited neurodegenerative disease, affecting ~20 in 10,000 people. A major class of proteins mutated in CMT patients is tRNA synthetases, enzymes that charge tRNAs with amino acids. However, some mutations that cause CMT do not reduce the ability of tRNA synthetases to catalyze this reaction. Recently, several tRNA synthetases associated with CMT were found to have conserved mRNA binding activity. It is possible that CMT could be caused by malfunction of the mRNA regulation by these proteins.

One mode of mRNA regulation by proteins is the localization of mRNA to large, stress-induced assemblies of RNA and protein called stress granules. Interestingly, some tRNA synthetases are found in these assemblies and aberrant stress granule dynamics are associated with a variety of neurodegenerative diseases. These observations raise the exciting possibility that CMT associated mutations in tRNA synthetases alter stress granule dynamics, leading to disease. Indeed, we find that yeast strains carrying a CMT associated mutation in Hts1 (histidine tRNA synthetase), form a significantly higher number of stress granules under stress conditions associated with high growth density. We are currently studying additional Hts1 mutations, as well as CMT causing mutations in tyrosine tRNA synthetase (Tys1). These assays will provide insights into the mechanisms of mRNA regulation by tRNA synthetases, and potentially yield new information about the causes of CMT.