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 Home / About Us > Dr Alexey Pshezhetsky > Review articles
Research Summary

1. MOLECULAR AND BIOCHEMICAL BASIS OF LYSOSOMAL STORAGE DISORDERS. My laboratory made a substantial contribution in the discovery of genes mutated in lysosomal storage diseases, hereditary conditions of children previously considered to be untreatable. We were the first to clone the gene for sialidase Neu1 which deficiency causes severe storage disease, sialidosis and to define the mechanisms causing sialidosis in patients. We characterized the lysosomal multienzyme complex containing sialidase, galactosidase, galacto-6-sulfatase and cathepsin A, deficient in GM1-galactosidosis, galactosialidosis and Morquio disease. Our studies explained the pathogenic mechanism of these genetic diseases, provided methods for their molecular diagnostics and revealed data that changed the view on the organization and functioning of lysosomal matrix enzymes. Most recently we have mapped the chromosomal position of the gene defective in another lysosomal disease, Mucopolysaccharidosis III C.
2. BIOGENESIS OF LYSOSOMAL ENZYMES. We identified structurally conserved surface regions in several lysosomal cathepsins and showed that they represent phosphotransferase recognition sites important for internalization and trafficking of these enzymes. The lysosomal sialidase, Neu1 was targeted to the lysosome through different mechanism, adapter protein-mediated vesicular pathway. We further demonstrated that in the immune cells i.e. activated T lymphocytes or differentiating monocytes Neu1 is directed to the cell surface, which may be potentially important for immune function.
3. PROTEOMICS AND FUNCTIONAL GENOMICS OF THE LYSOSOME. We have defined the proteomes of the lysosomal membrane and matrix, as a part of global Cell Map established by the Montreal Proteomics Network. The goal of this project funded by Genome Quebec is to identify the resident and associated proteins of all organelles and molecular machines of the eukaryotic cell by large-scale proteomics. These studies have defined a new lysosomal sialidase Neu4, important for developing new therapies for sialidosis and galactosialidosis. In complementary studies, using RNA arrays, we have identified genes, whose expression is induced or silenced in the cells of patients affected with lysosomal storage and defined that impairment of the ubiquitin-dependent protein degradation pathway represents a common pathogenic mechanism.
4. COMPARATIVE PROTEOMICS OF HUMAN DISEASES. I am a director of the Sainte-Justine Hospital Proteomics Laboratory, which was established using my Canadian Foundation for Innovation grant. We use proteomics-based technology for diagnostics and for discovery of targets for treatment and prevention of human diseases. We collaborate with researchers from gastroenterology (proteomics of disorders of the bile ducts), genetics (proteomics of the fat cell implicated in paediatric obesity), medicine (proteomics of the blood vessel wall in hypertension), and paediatric oncology (proteomics of leukaemia cells). In the project funded by Genome Quebec/Genome Canada we use proteomics to identify candidate genes for susceptibility to T2 Diabetes Mellitus. Our studies of proteomes of blood vessel cells helped to establish new signalling pathways for arterial vasculature whereas functional proteomic study of the fat tissue defined a new major adipocyte lipase.
5. DEVELOPMENT OF NEW PROTEOMIC TECHNOLOGY. We have developed a new technology for quantification of proteins in a proteome. This method based on peptide labelling with stable isotopes provides effective and accurate quantification of proteins and is also useful for the analysis of their post-translational modifications, as well as for the study of protein-protein interactions.
6. CLINICAL RESEARCH. For almost 4 years I am a Scientific Supervisor of the Medical Genetics Diagnostic Laboratory at Ste-Justine Hospital that performs analyses on patients with inherited lysosomal and metabolic disorders. Together with the personal of the laboratory we develop new biochemical and enzymatic tests.



Montreal Diabetes Research Center 2008
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