TO REPAIR OR TO DIE: THE CELLULAR RESPONSE TO RIBOSOMOPATHY-CAUSING MUTATIONS

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Proteins, a diverse set of molecules that are essential for life, are made up of building blocks (amino acid), assembled in a sequence dictated by genes. Genes direct the production of messenger RNA which are then used as a template for protein synthesis by sophisticated nanomachines called ribosomes. In the absence of ribosomes, e.g. when one of their 83 constituents is missing, life cannot be sustained. Partial ribosome deficiency, e.g. when one constituent is defective or in reduced amount, can often be tolerated, although it is associated with a variety of diseases collectively known as ribosomopathies. These encompass a large number of syndromes that each affect predominantly specific tissues such as the blood, bones, the brain and more. It has been assumed that these symptoms stem largely from the cells' inability to produce sufficient protein. We found however that, in an animal model of ribosomopathy, cells display many markers of cellular stress that is normally caused by the accumulation of defective proteins. We have suggested that the need to remove defective ribosomes overwhelms the cellular machinery that normally destroys other defective proteins. Thus, defective proteins accumulate, impairing the cell's activity, much like interruptions of curb-side waste collection affect city life. Within a ribosome-deficient tissue, some cells undergo apoptosis (a form of cell suicide), while others survive and learn to live with chronic stress. We are proposing to use our animal model as well as cells from patients to decipher the molecular machinery that detects the presence of defective ribosomes and controls the decision between cell death and repair. By understanding the molecular pathways that cells activate in response to defective ribosomes, we will infer ways to boost their protective response, especially in neurons, a type of cells that are particularly sensitive to the presence of defective proteins. We expect that our results will open up new therapeutic avenues to alleviate the symptoms of ribosomopathies and possibly other proteinopathies.