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A study by the Kaether research group at the Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) in Jena sheds light on the molecular mechanisms of a rare and usually fatal hereditary disease called MEDS1. The study entitled "IER3IP1-mutations cause microcephaly by selective inhibition of ER-Golgi transport", now published in the open access journal "Cellular and Molecular Life Sciences", show for the first time that the absence of IER3IP1 or its mutation causes defective transport of certain proteins that are essential for the development and survival of nerve cells.
Jena. A study entitled "IER3IP1-mutations cause microcephaly by selective inhibition of ER-Golgi transport", now published in the open access journal "Cellular and Molecular Life Sciences", provides new insights into the molecular causes of a rare and usually fatal hereditary disease called MEDS1. The disease is characterized by microcephaly (a head that is too small with a simplified brain pattern), epilepsy and diabetes. Affected children usually die at an early age. The underlying cause is mutations in the IER3IP1 gene, which codes for a small protein in the membrane of the endoplasmic reticulum (ER). This protein plays a crucial role in the transport of molecules between the ER and the Golgi apparatus.
The results of the study show for the first time that the absence of IER3IP1 or its mutation causes defective transport of certain proteins that are essential for the development and survival of nerve cells. Furthermore, the absence of IER3IP1 leads to an expansion of the ER membranes and increased lysosome activity. In addition, the scientists led by research group leader Dr. Christoph Kaether found that the transport of certain sorting proteins, ERGIC53 and the KDEL receptor 2, is disrupted, which leads to defective secretion of ER proteins - an aspect that was not previously associated with IER3IP1.
New findings for basic research
The Jena researchers' findings are particularly relevant for basic research and expand our understanding of brain development. Although MEDS1 is a very rare disease and the results do not yet offer any direct therapeutic approaches, they open up new possibilities for research into similar mechanisms. Of particular interest here is the parallel to a related protein, YIPF5, which performs similar functions and whose mutation can cause a very similar disease. The knowledge gained could therefore also be of significance for other neurobiological projects.
Challenges and new technological approaches
"The elucidation of these complex relationships was extremely challenging, especially from a technical perspective," says Dr. Kaether. However, advances in proteomics and cell surface analysis have enabled the team to measure the subtle differences in protein transport and the specific changes in cell structure caused by the absence of IER3IP1.
Potential approaches for future therapies
Although the results of this study primarily contribute to basic research, they also provide starting points for potential therapeutic strategies against similar diseases. These include approaches such as the targeted correction of protein transport, modulation of the ER stress response or gene therapy.
Further Information
The Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) – upon its inauguration in 2004 – was the first German research organization dedicated to research on the process of aging. Around 350 employees from around 40 nations explore the molecular mechanisms underlying aging processes and age-associated diseases. For more information, please visit www.leibniz-fli.de.
The Leibniz Association connects 97 independent research institutions that range in focus from natural, engineering, and environmental sciences to economics, spatial, and social sciences and the humanities. Leibniz Institutes address issues of social, economic, and ecological relevance. They conduct basic and applied research, including in the interdisciplinary Leibniz Research Alliances, maintain scientific infrastructure, and provide research-based services. The Leibniz Association identifies focus areas for knowledge transfer, particularly with the Leibniz research museums. It advises and informs policymakers, science, industry, and the general public. Leibniz institutions collaborate intensively with universities – including in the form of Leibniz ScienceCampi – as well as with industry and other partners at home and abroad. They are subject to a transparent, independent evaluation procedure. Because of their importance for the country as a whole, the Leibniz Association Institutes are funded jointly by Germany’s central and regional governments. The Leibniz Institutes employ around 20,500 people, including 11,500 researchers. The financial volume amounts to 2 billion euros. For more information: www.leibniz-gemeinschaft.de/en/.
DOI: https://doi.org/10.1007/s00018-024-05386-x
Research Group Leader Dr. Christoph Kaether
Nadine Grimm/FLI
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Research Group Leader Dr. Christoph Kaether
Nadine Grimm/FLI
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