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Studying the Molecular Mechanism of Mitochondrial Aminoacyl tRNA Synthetases in Neurons


Project Description

Aminoacyl-tRNA synthetases (ARSs) are essential and ubiquitous ‘house-keeping’ enzymes responsible for charging amino acids to their cognate tRNAs and provide the substrates for global protein synthesis in the cytosol and mitochondria. Mutations in each of the 19 human mitochondrial and many of the cytosolic ARS genes have been reported in human disease. Glycyl- (GARS) and lysyl tRNA (KARS) synthetase genes encode both cytosolic and mitochondrial ARS enzymes, suggesting links between protein syntheses in these two distinct cellular compartments. Despite being ubiquitously expressed, mutations in these genes show an unexpected variety of phenotypes, including many neurological disorders affecting the white matter, causing epileptic encephalopathy, pontocerebellar hypoplasia, peripheral neuropathy or intellectual disability, while other characteristic phenotypes affect other organs. The cause of the selective vulnerability, or the exact molecular mechanisms leading to such tissue specific clinical manifestations are poorly understood.

In human cells, two distinct groups of ARSs encoded by separate genes can be distinguished by their cytoplasmic or mitochondrial localization however, GARS (glycyl tRNA synthetase) and KARS (lysyl tRNA synthase) are bi-functional enzymes functioning in both mitochondrial and cytosolic translation. This project focuses on the molecular mechanism of tissue specific manifestations in mitochondrial and bi-functional tRNA synthetase-associated mutations by investigating substrates and signalling pathways involved in the protein translation axis. We use human neuronal cell lines derived from patient fibroblasts to model the defect in neurons. Furthermore, ARSs have been described to have non-canonical functions which will be further investigated by identifying new binding partners.

Funding Notes

Funding deadline is 3rd December 2019 for start in October 2020. When applying indicate on the application the funding options (GATES USA *deadline 9/10/19*, Gates Cambridge or other Cambridge Funders). Home/EU and International applications are all considered for funding.

References

D’Souza AR, Minczuk M. Mitochondrial transcription and translation: overview. Essays Biochem. 2018 Jul 20;62(3):309-320.

Boczonadi V, Ricci G, Horvath R. Mitochondrial DNA transcription and translation: clinical syndromes. Essays Biochem. 2018 Jul 20;62(3):321-340. Print 2018 Jul 20. Review.

Applicants can only be considered if they apply via the applicant portal which can be found at this link; https://www.graduate.study.cam.ac.uk/ please do not send in an enquiry and CV as this will not be considered an application.

Boczonadi V, Meyer K, Gonczarowska-Jorge H, Griffin H, Roos A, Bartsakoulia M, Bansagi B, Ricci G, Palinkas F, Zahedi RP, Bruni F, Kaspar B, Lochmüller H, Boycott KM, Müller JS, Horvath R. Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons. Hum Mol Genet. 2018 Jun 15;27(12):2187-2204.

Boczonadi V, Jennings MJ, Horvath R. The role of tRNA synthetases in neurological and neuromuscular disorders. FEBS Lett. 2018 Mar;592(5):703-717.

Related Subjects

How good is research at University of Cambridge in Clinical Medicine?

FTE Category A staff submitted: 192.05

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