Protein homeostasis, or proteostasis, is maintained within the cell thanks to the balance, controlled by a proteostasis network (PN), between protein synthesis, folding and degradation. All factors that constitute this PN ...
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Protein homeostasis, or proteostasis, is maintained within the cell thanks to the balance, controlled by a proteostasis network (PN), between protein synthesis, folding and degradation. All factors that constitute this PN act in a coordinated manner to ensure proteostasis integrity and consequently cell function. Conversely, a proteostasis unbalance may lead to some diseases such as Alzheimer's, Parkinson's, Cancers or Alpha 1-Antitrypsin deficiency (AATD).More precisely, AATD is due to mutations in the SERPINA1 gene resulting in misfolding AAT protein leading to its retention in the endoplasmic reticulum (ER) of hepatocytes and to a defect in trafficking and secretion of the AAT mutated forms in the extracellular space. The retention and accumulation of these variants triggers intracellular injury cascade, cell death and chronic liver damage (cirrhosis, cancer).The severity of the liver disease ranges from transient neonatal cholestasis to cirrhosis and cancers. About 10% of AATD patients have a severe liver outcome (portal hypertension, liver failure, liver transplantation or death) leading to liver transplantation, unique therapeutic strategy available in AATD-mediated liver disease. Given, this low pourcentage and since all the patients share the same genotype, the presence of modifiers (genetic, environnement) in the onset of severe AATD liver disease is now well recognized despite they still remain to be identified.Thus, the goal of my thesis project was to identify these modifiers to develop new therapeutic approaches and early non-invasive diagnostic methods (biomarkers).To achieve this goal, firstly, I identified protein disulfide isomerase (PDI) family members, and particularly PDIA4, are upregulated and involved in AATD-mediated liver disease in adults. PDI inhibition upon cysteamine or siRNA treatments leads to improvements in features of AATD and hence represents a therapeutic approach for treatment of AATD-mediated liver disease.Concurrently, I participated in a candidate gene study with the SORL1 gene, already identified as risk factor in early-onset Alzheimer's disease. A particular SORL1 micro-haplotype constituted with 3 SNP was genotyped on 86 AATD children. Interestingly, the mutated form of this micro-haplotype was associated with lower occurrence of severe liver disease. In agreement, in cellulo studies showed that SORL1 influences AATD features. These data suggest that the mutated form of SORL1 micro-haplotype may partly prevent from severe liver disease in AATD children and represents a potentiel marker in the onset of liver disease in AATD children.Finally, the last part of my thesis project focused on the characterization of the role of the proteasome in the proteotoxicity associated with AATD liver damage. My preliminary data suggest an alteration of proteasome in AATD-mediated liver disease compensated by the specific pathway induction of this machinery.Altogether, my thesis results have improved our understanding on the cellular and molecular mechanisms involved in AATD liver disease and have pinpointed new therapeutic targets and treatments.
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