What role does a tRNA modification complex, called Elongator, play in brain development?
SOLARIS Centre users from the Malopolska Centre of Biotechnology (of the Jagiellonian University, together with Australian, Turkish and Canadian colleagues, have found a link between defects in the cellular protein production machinery and neurodevelopmental disorders (NDDs), characterized by an inability to reach cognitive and motor milestones. Key studies in this publication were conducted using Cryo-EM microscopes located at our center.
The speed rate of protein synthesis is crucial to the integrity of the proteome
Scientists showed how genetic mutations in patients affect the Elongator activity and lead to severe clinical symptoms. The study provided the first clinical evidence for missense mutations in the Elongator accessory subcomplex ELP456 to cause neurodevelopmental disorders. Genome-wide analysis allowed identification of pathogenic variants in patients with severe clinical presentation of NDDs. Further modelling of the patient-derived mutations in mice resembled the complex neurodevelopmental phenotype and revealed neuron-specific consequences of the found genetic mutations.
„We report patient-derived substitutions in the accessory ELP456 subcomplex to affect different types of neurons than previously known mutations in the catalytic core of the complex” – explains Dr. hab. Sebastian Glatt, the senior author and head of the Max Planck Research Group, that carried out the experimental work in Krakow. This provides a novel concept in the field that depletion of specific tRNA modifications in patient cells may induce specific changes in the cellular proteomes.
Read more on the SOLARIS website