Talk Abstracts

Talk on Saturday 09:30-09:45am submitted by Nien-Ching Han

Elucidating the mechanism of BMAA misincorporation and its impact on translation

Nien-Ching Han (Department of Microbiology, The Ohio State University), Tammy J. Bullwinkle (Department of Microbiology, The Ohio State University), Kaeli F. Loeb (Department of Microbiology, The Ohio State University), Kym F. Faull (Pasarow Mass Spectrometry Laboratory, University of California at Los Angeles), Michael Ibba (Department of Microbiology, The Ohio State University)

Abstract:
beta-N-methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid that has been associated with neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). BMAA has been found in human protein extracts, however, the mechanism by which it enters the proteome is still unclear. It has been suggested that BMAA is misincorporated at serine codons during protein synthesis, but no direct evidence has ever been shown. Here, using LC-MS purified BMAA, we sought to identify which aaRS will utilize BMAA as a substrate for aminoacylation. Despite BMAA’s previously predicted misincorporation at serine codons, following a screen for amino acid activation, we observed that BMAA is not a substrate for human SerRS. Instead, we showed that BMAA is a substrate for human AlaRS and is able to form BMAA-tRNA^Ala, while escaping from the intrinsic AlaRS proofreading activity. Furthermore, we found that BMAA acts as an inhibitor to both the cognate amino acid activation and the editing function of AlaRS. These results reveal that BMAA disrupts the integrity of protein synthesis through multiple different pathways, hence may be more problematic than previously suggested.

Keywords: BMAA, aminoacyl-tRNA synthetase, non-cognate amino acids