Investigating the effect of UBA1 on tRNA ligases in neuromuscular disorders

Dinja van der Hoorn 1, 2, Hannah K Shorrock 1, 2, Ewout JN Groen 1, 2, Penelope Boyd 1, 2, Maica Llavero Hurtado 3, Douglas J Lamont 4, Thomas M Wishart 1, 3, Thomas H Gillingwater 1, 2

  1. Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK
  2. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK
  3. Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK
  4. FingerPrints: Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, UK.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, involving the degeneration of motor neurons. Due to this degeneration, SMA is characterized by muscle weakness. It has been demonstrated that ubiquitin-like modifier activating enzyme 1 (UBA1) is decreased in SMA. UBA1 activates ubiquitin in the ubiquitin-proteasome pathway that leads to protein targeting and degradation. It has been shown through a proteomics study that UBA1 also influences the expression of tRNA ligases. This together can indicate a role of tRNA ligases in SMA, under the influence of UBA1. Two tRNA ligases, tyrosyl- (YARS) and glycyl-tRNA ligases (GARS) have been shown to be involved in Charcot-Marie-Tooth disease (CMT), which is a neuromuscular disorder that shows similarities with SMA. In this study we continue to investigate the influence of UBA1 expression on YARS and GARS, by investigating the expression of YARS and GARS in SMA tissue and tissue that overexpresses UBA1. This expands our understanding of the effect of UBA1 on the expression of YARS and GARS in vivo and therefore the role of these tRNA ligases in SMA and CMT.

References

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  2. Powis RA, Karyka E, Boyd P, Come J, Jones RA, Zheng Y, et al. Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. JCI insight. 2016;1(11):e87908.
  3. Groen EJ, Gillingwater TH. UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration. Trends in molecular medicine. 2015;21(10):622-32.
  4. Motley WW, Talbot K, Fischbeck KH. GARS axonopathy: not every neuron's cup of tRNA. Trends in neurosciences. 2010;33(2):59-66.
  5. Jordanova A, Irobi J, Thomas FP, Van Dijck P, Meerschaert K, Dewil M, et al. Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nature genetics. 2006;38(2):197-202.

Funded by: This work was supported by research grants from the Euan MacDonald Centre for Motor Neuron Disease Research, Muscular Dystrophy UK and the UK SMA Research Consortium (SMA Trust)

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