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Our main focus is on endoplasmic reticulum (ER) quality control retention and ER-associated degradation (ERAD) of proteins and the generation of ER stress in mammalian cells. These processes are involved in the normal biogenesis of membrane and secretory proteins as well as in the development of many diseases where genetic or environmental causes lead to protein misfolding and accumulation in the ER (ER stress). Our research involves the study of membrane and secretory protein folding in cells in vivo and the role of molecular chaperones. We have been interested in the mechanism of recognition and delivery of the substrates from the ER to the cytosolic proteasomes and the involvement of glycan processing as a signal in the timing of glycoprotein ERAD. Our discovery of the ER quality control compartment (ERQC), where the substrates are first concentrated has opened a new dimension in the studies of protein trafficking and quality control in the early secretory pathway.

In a related applied project we have found a protein secreted exclusively by the liver, the levels of which vary dramatically in liver disease (hepatitis, cirrhosis, obesity), constituting a useful non-invasive diagnostic marker for the development of these diseases.

We have been investigating the genesis of ER stress in protein misfolding diseases, particularly in neurodegenerative diseases (e.g. Huntington’s disease (HD)). This has allowed us to determine that soluble oligomeric forms of the misfolded protein cause ER stress in HD, leading in the long term to cell death, whereas the final large aggregates are cell protective. We have devised a therapeutic strategy by interfering with the unfolded protein response (UPR), which is induced by the ER stress in striatal neurons in HD.

Mechanisms of protein quality control in the early secretory pathway

and the genesis of ER stress