Research co-funded by the Foundation for Polish Science, conducted by scientists at the Max Planck Laboratory at the Małopolska Centre of Biotechnology (MCB) of the Jagiellonian University in Krakow in collaboration with Queensland University, Brisbane, Australia, sheds a new light on the molecular and genetic basis for severe neurological disorders in humans. The findings have recently been published in Nature Communications.

For the past three years, researchers have been trying to better understand the relationship between mutations in the gene encoding one of the Elongator complex subunits and development of microcephaly, intellectual disability, and autism spectrum disorders. “Elongator is a large protein complex comprising multiple subunits. Its function is to introduce chemical modifications in tRNA molecules, which in turn play a key role in translation, a process that regulates the production of all proteins in living organisms,” says Tomasz Gawda, graduate student working at the Max Planck Research Group and the paper’s second author. “While it is known that mutations within any of the complex subunits are associated with several neurological diseases in humans, their underlying molecular mechanisms have been poorly defined,” adds Monika Gaik, Ph.D.

With a multidisciplinary approach the scientists were able to combine clinical data of patients in Australia, Denmark, Germany, the United States, and France with in vivo experiments using mouse models involving detailed brain imaging and behavioural tests. Alongside biomedical data, the work of seven Polish scientists was crucial. They conducted advanced biochemical analyses of purified human Elongator complex, which made it possible to demonstrate, at the molecular level, direct consequences of mutations identified in patients with neurodevelopmental disorders.

The published results clearly show that mutations in the Elongator complex subunit 2 (Elp2) found in patients inhibit the enzymatic activity of the entire complex and have direct consequences for human brain development. “This was the first time we were able to purify this large human protein complex and conduct direct laboratory analysis of the detrimental effects of mutations that perturb its function. Through biochemical and biophysical analyses we were able to confirm that the Elongator complex is indeed responsible for the occurrence of specific clinical phenotypes,” says Sebastian Glatt, Ph.D., corresponding author and leader of the MCB research group, who initiated and coordinated the whole project in collaboration with Professor Brandon J. Wainwright of IMB Brisbane.

The findings described in the paper reveal in detail the previously uncharted landscape of the highly complex aetiology of intellectual disability and autism, as well as the fundamental role of the Elongator complex in humans. The new information will be a boost to scientists worldwide in their search for diagnostic markers and potential interventional treatments for these severe neurological disorders.

The research was co-funded by the Foundation for Polish Science under the FIRST TEAM and TEAM-TECH Core Facility grants awarded to Sebastian Glatt, Ph.D., from the resources of the Smart Growth Programme within the framework of the European Regional Development Fund.

Source: The Foundation for Polish Science