Unlocking mt-tRNA Synthetases: Impact on Neurodegeneration

Summary

Making proteins is fundamental for energy production, fighting disease, growth and development. In a family of rare, neurodegenerative diseases, known as mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) diseases, this process is disrupted at its most fundamental level: the attachment of amino acid ‘building blocks’ to the growing protein. 

Mt-aaRS diseases affect the mitochondria of the cell, disrupting energy production. In each disease variant, it is the attachment of a different amino acid that is inhibited, resulting in a diverse array of problems affecting different organs in the body. For example, deficiency in the attachment of one amino acid might lead to heart failure, while deficiency in another to neurodegeneration, seizures, ataxia or spasticity. Research in mt-aaRS diseases has been largely focused on studying individual variants. This project will study neurodegenerative mt-aaRS diseases in the laboratory, to understand this disease family holistically. 

Project aims

Our aim is to build a comprehensive database of mt-aaRS mutations including children afflicted worldwide and utilize cutting edge technologies including human brain organoids, single cell transcriptomics, zebrafish models, gene editing and advanced bioinformatics to identify the biological pathways and understand why the brain is more affected while other organs protected. The student will have the opportunity to establish 2D and 3D (brain organoids) neuronal models of mt-aaRS diseases to better understand tissue specific presentations. 

Knowledge gained through each of these components will guide targeted therapies for patients with mt-aaRS and other neurodegenerative mitochondrial diseases affecting nearly 1.5 million worldwide. 

References

Podmanicky O, Gao F, Munro B, Jennings MJ, Boczonadi V, Hathazi D, Mueller JS, Horvath R. Mitochondrial aminoacyl-tRNA synthetases trigger unique compensatory mechanisms in neurons. Hum Mol Genet. 2024 Feb 18;33(5):435-447. 

Del Greco C, Antonellis A. The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease. Genes (Basel). 2022 Dec 9;13(12):2319. 

Trial Readiness in Ataxia Telangiectasia (AT) (PhD & MPhil) 

Supervisor: Prof Rita Horvath and Dr Anke Hensiek 

Contact details

Professor Rita Horvath, rh732@medschl.cam.ac.uk - Neurology

Co-supervisor: Dr Denisa Hathazi

Opportunities

This opportunity is open to PhD applicants.