Logistics in the brain

Brain cells can produce proteins everywhere, even in their long branches. Neurones without this ability cause severe neurological disorders that can lead to disability and epilepsy. The research groups led by Marino Zerial, Max Planck Institute (MPI) of Molecular Cell Biology and Genetics in Dresden, and Stefan Raunser, MPI of Molecular Physiology in Dortmund, together with researchers from the MPI of Brain Research in Frankfurt am Main, have now discovered a new form of the disease;für Hirnforschung in Frankfurt am Main and the MPI of Multidisciplinary Natural Sciences in Güttingen have discovered a new transport mechanism that brings messenger RNA (mRNA), the blueprint of proteins, to the right place  in neurons. Using a series of techniques, the researchers have identified a protein complex called FERRY, which connects mRNA to intracellular carriers, and elucidated its role and structure. The discovery could lead to a better understanding of neurological disorders and potentially to new medical applications.

Far away and yet so close!

„This is a major step forward in elucidating the mechanisms underlying mRNA distribution in brain cells“, says Marino Zerial, Director at the MPI in Dresden. Cells produce vital proteins using mRNA as a blueprint and ribosomes as 3D printers. But brain cells have a logistical challenge to overcome: they have a tree-like shape with branches that can extend over centimetres in the brain. This means that thousands of mRNAs have to be transported far away from the cell nucleus, which is similar to the logistical effort involved in supplying all the supermarkets of an entire country," says Jan Schuhmacher, first author of the study.

So far, researchers have attributed the role of the transporter to spherical compartments inside the cell, the so-called late endosomes. However, the Max Planck researchers show that another type of compartments, the early endosomes (EEs), are also suitable as mRNA carriers due to their ability to travel in both directions in the intracellular road network. In the first publication, led by Marino Zerial, the researchers discovered the function of a protein complex that they called FERRY (Five-subunit Endosomal Rab5 and RNA/ribosome intermediarY). In neurons, FERRY is associated with EEs and functions in a similar way to a tether during transport: it interacts directly with the mRNA and attaches it to the EEs, which thus become logistical triggers for the transport and distribution of mRNA in the brain cells

But how does FERRY bind to the mRNA? This is where Stefan Raunser's group at the MPI Dortmund comes into play. In the second publication, Dennis Quentin and his colleagues used cryo-electron microscopy (cryo-EM) to decipher the structure of FERRY and thus the molecular properties that enable the complex to bind to both EEs and mRNAs. The resulting 3D atomic model of FERRY with a resolution of 4 atoms shows a novel RNA binding mechanism involving coiled-coil domains. The researchers were also able to clarify how some genetic mutations affect the ability of FERRY to bind mRNA, leading to neurological disorders. Our research lays the foundation for a more comprehensive understanding of neurological disorders caused by failed mRNA transport or defective mRNA distribution, which could also lead to the identification of therapeutically relevant targets," says Raunser.

Article from the "Max Planck Society" from 01/06/2023