New Hope for Alzheimer’s and Parkinson’s Patients
Researchers from the Technion’s Faculty of Biology have discovered new mechanisms that affect protein synthesis folding and assembly in cells - processes essential for proper function and the prevention of neurodegenerative diseases
Most proteins in the body’s cells do not function alone but act together as complexes to achieve concerted functions. When the formation of these complexes is impaired, various diseases can develop, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Technion researchers used innovative methods to “capture” proteins in the cell during their synthesis because proteins are particularly vulnerable at this stage – during translation by the ribosome. Ribosomes in cells were analyzed using ribosome profiling, a method that sequences the mRNA being translated by the ribosomes at single-codon resolution, combined with advanced microscopy and proteomics analysis of the resulting proteins. The researchers also used simulations of the protein folding process and interactions with other proteins to form complexes at the atomic level (molecular dynamics). This led to the discovery of a mechanism that protects proteins from misfolding during their production.
In the diagram: The ribosome (in green) with the newly formed complex: N-Acetyl Transferase (NAT) A, consisting of a catalytic subunit (in yellow) and an auxiliary subunit (in gray). Interaction areas with the ribosome, chaperones acting on the ribosome, and between subunits are indicated in light blue.
The researchers found that the folding and assembly of protein complexes depends on only a few amino acids. Characterization of these amino acids revealed that they can form highly stable interactions and serve as anchors to initiate the assembly of functional protein complexes in the cell. They discovered that this process occurs during protein synthesis. Furthermore, if the assembly process on the ribosome is disrupted and these amino acids are left alone, they can destabilize the entire protein and cause it to misfold. The researchers found that this mechanism is evolutionarily conserved, from yeast to humans, indicating that mutations in amino acids serving as “anchors” for initiating protein-protein interactions on the ribosome are found in various developmental and neurodegenerative diseases.
In the diagram: The new mechanism in action: during protein production by the ribosome, exposure of individual amino acids initiates the folding process and interaction with cellular proteins. These amino acids are characterized by their ability to form highly stable interactions and serve as anchors for the assembly of functional protein complexes in the cell. The connection between the protein being produced and its partners protects it from misfolding and maintains its stability at its most vulnerable stage. The process is evolutionarily conserved, so mutations in amino acids serving as “anchors” for initiating protein-protein interactions on the ribosome lead to diseases.
Based on these results, the researchers developed a model to predict such essential anchors required for creating interaction networks in cells and protecting cellular protein production processes. This model could serve as a basis for designing new proteins. By focusing on early events during protein creation, the researchers identified targets that could enable the development of preventive treatments for neurodegenerative diseases.
From right to left: Dr. Fabian Glaser, student Hila Ben-Arie Zilberman, Dr. Hagit Bar-Yosef, student Johannes Venezian, and Dr. Ayala Shiber
The research, led by Dr. Ayala Shiber, was spearheaded by student Johannes Venezian, along with Dr. Hagit Bar-Yosef and student Hila Ben-Arie Zilberman from the Shiber lab, in collaboration with Prof. Oded Kleifeld’s lab from the Faculty of Biology, student Noam Cohen from Kleifeld’s lab, Dr. Fabian Glaser from the Technion Center for Structural Biology-Computational Biology (TCSB-THHI), and Prof. Juan Fernandez Recio from Spain. The paper on this topic was published in the prestigious journal Nature Communications: