MECHANISM OF TRANSMEMBRANE INTEGRATION OF TAIL-ANCHORED PROTEINS INTO THE ENDOPASMIC RETICULUM: CHARACTERIZATION OF A NOVEL MECHANISM OF MEMBRANE BIOGENESIS AND ITS IMPLICATIONS FOR ER PHYSIOLOGY AND PATHOLOGY

Eukaryotic cells, which are the building blocks of all multicellular organisms, are characterized by the presence of numerous membrane-bounded subcompartments, or organelles, that are necessary for the efficient execution of the multiple enzymatic reactions that constitute the hallmark of life. Each organelle is endowed with a characteristic protein set. which determines its functional properties. However, the majority of proteins are not synthesized within the organelle where they operate and must therefore be transported from their site of synthesis to their final compartment of residence. This is the problem of so-called protein traffic, whose proper functioning is key to organelle biogenesis and physiology. In the post-genomic era, in which genes linked to hereditary diseases are being discovered with increasing speed, numerous mutations that alter protein localization have been discovered. These genes cause diseases due to defects in protein traffic. In this project, we will focus on a protein called VAP-B, of which a mutation causes a familial form of amyotrophic lateral sclerosis (ALS), ALS8. This poorly understood fatal disease is characterized by the selective degeneration of motor neurons. In ALS8, the VAP-B protein, which normally localizes to the membranes of a compartment called Endoplasmic Reticulum, is found at a different, uncharacterized, intracellular site. In this project, we will attempt to elucidate how Endoplasmic Reticulum proteins similar to VAP-B reach their intracellular destination, and the nature of the defect causing the incorrect localization of mutant pathogenic VAP-B. We envisage that the elucidation of the pathogenic mechanism of VAP-B will lead to a better understanding of the more common, sporadic, form of ALS and to new therapeutic perspectives for these terrible diseases.