Researchers from the Max Planck Institute (MPI) of Molecular Cell Biology and Genetics in Dresden, in collaboration with colleagues from other MPIs, have made a significant discovery regarding the delivery mechanism of messenger RNA (mRNA) in neurons. The absence of this mechanism in neurons can lead to severe neurological disorders such as epilepsy and disability.
Through their research, the scientists identified a protein complex called FERRY, which plays a crucial role in linking mRNA to intra-cellular carriers. They have also gained insights into the structure and function of this protein complex. This discovery has the potential to enhance our understanding of neurological disorders resulting from malfunctioning of the FERRY complex and could open up new avenues for medical intervention. The findings have been published in two consecutive papers in the journal Molecular Cell.
Marino Zerial, leading the study at the MPI in Dresden, emphasizes the significance of these publications in unraveling the mechanisms behind mRNA distribution in brain cells. mRNA serves as a blueprint for the production of essential proteins, with ribosomes acting as the 3D printers. However, the logistical challenge for brain cells arises from their intricate, tree-like structure, with long branches spanning centimeters in the brain. This necessitates the transportation of thousands of mRNAs from the nucleus to distant locations within the cell, akin to the complex task of supplying supermarkets across an entire country, as described by Jan Schuhmacher, the first author of the study.
Previously, researchers believed that spherical compartments called Late Endosomes played the role of mRNA carriers. However, the MPI scientists argue that another type of compartment known as Early Endosomes (EEs) is also suitable for transporting mRNA due to their ability to travel bidirectionally along intracellular networks.
The first publication, led by Marino Zerial, shed light on the function of the FERRY protein complex. In neurons, FERRY interacts with EEs and functions as a secure strap during transport. It directly binds to mRNA, ensuring its attachment to EEs, which subsequently act as carriers for the transportation and distribution of mRNA in brain cells.
Stefan Raunser’s team from the MPI Dortmund played a crucial role in uncovering how the FERRY protein complex binds to mRNA. In their publication, led by Dennis Quentin and colleagues, they utilized cryo-electron microscopy (cryo-EM) to determine the structure of FERRY and identify the molecular features responsible for its interaction with both EEs and mRNAs. By achieving a remarkable resolution of 4 Ångstroms, they developed a detailed 3D atomic model of FERRY, unveiling a unique RNA binding mechanism that involves coiled-coil domains.
Furthermore, the researchers investigated how specific genetic mutations can impact FERRY’s ability to connect with mRNA, consequently leading to neurological disorders. This groundbreaking research lays the foundation for a more comprehensive understanding of the molecular basis behind mRNA transport and distribution failures in neurological disorders. It also holds the potential to identify potential therapeutic targets for intervention, as highlighted by Stefan Raunser.
Source: Max Planck Society