Contact info

Dr Alexey Pshezhetsky
CHU Sainte-Justine, Research Center
3175, C�te Ste-Catherine Road - Room 6722
Montreal, QC H3T 1C5

Tel: 1-514-345-4931 ext 2736
Fax: 1-514-345-4766
E-mail: [email protected]

Link to Pshezhetsky Lab webpage

Research keywords

Dr Alexey Pshezhetsky graduated from the Department of Chemistry, Moscow State University in 1985. In 1989 he obtained his PhD in chemical kinetics and catalysis from the same university. In 1989-1990 Dr Pshezhetsky was a post-doctoral fellow in Moscow Institute of Medical and Biological Chemistry, Russian Academy of Medical Science. During this time he studied the lysosomal storage diseases, severe progressive diseases of children caused by the inherited deficiencies of lysosomal enzymes. Dr Pshezhetsky continued his studies of lysosomal enzymes as a researcher in the A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, where he also investigated immunoregulation of alcohol consumption.

In 1993 Dr Pshezhetsky joined Montreal University (Department of Pediatrics and Department of Medical Genetics, Ste-Justine Hospital) where he was subsequently promoted to Research Professor. He is also affiliated with the Department of Biochemistry, Montreal University and Department of Anatomy & Cell Biology McGill University. Since 1998 he is a scientific supervisor of Medical Genetics Diagnostic Laboratory and a director of a Proteomics Core Laboratory at Ste-Justine Hospital. The research of Dr Pshezhetsky has been acknowledged by many national and international agencies including the Canadian Institutes of Health Research (CIHR), Canadian Foundation for Innovation (CFI), Genome Canada, Genome Quebec, Valorisation Research Quebec, Vaincre les Maladies Lysosomales (France), Sanfilippo foundation and others. Dr Pshezhetsky received many career awards and fellowships including FRSQ Scholarships, Chercheur-boursier junior 2 and Chercheur-boursier senior. In 2001 he received an Award of Excellence in Pediatric Research from Foundation for the Research in Children's Disorders and, in 2002, became a recipient of a National Investigator Award from FRSQ. In JDRF center Dr Pshezhetsky in collaboration with other researchers uses proteomics to identify candidate genes for susceptibility to T2DM.

1. Molecular and biochemical basis of lysosomal storage disorders. My laboratory made a substantial contribution to 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 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 mechanisms of these diseases, provided methods for their molecular diagnostics and revealed data that changed the view on the organization and functioning of lysosomal matrix enzymes (J Biol Chem 1996 271:28359; Nat Genet 1997 15:316; Hum Mol Genet 1998 7:115; Hum Mol Genet 2000 9:1075; J Biol Chem 2001 276:17286; Hum Mutat 2003 22(5):343). Recently we have also discovered the gene defective in another lysosomal disease, Mucopolysaccharidosis III C (J Med Genet 2004 41:941; Am J Hum Genet 2006 79:807). We also established that impairment of the ubiquitin-dependent protein degradation pathway represents a common pathogenic mechanism in lysosomal storage diseases (Cell Death Differ, 2007 14:511).

2. Lysosomal enzymes. We identified a structurally conserved phosphotransferase recognition sites in lysosomal cathepsins A, C and D important for proper trafficking of these enzymes (Biochemistry 1999 38:73). We found that the lysosomal sialidase, Neu1 was targeted to the lysosome through adapter protein-mediated vesicular pathway (J Biol Chem 2001 276:46172). We further demonstrated that Neu1 is also targeted to the cell surface, where it plays a role in activation of immune receptors and formation of elastic fibers (J Biol Chem 2006 281:3698; J Biol Chem 2006 281:27526; FEBS J 2006 272:2545). Most recently we provided the first evidence that cathepsin A acts in vivo as endothelin-1-inactivating enzyme and confirmed a crucial role of this enzyme in effective elastic fibre formation (Circulation, 2008 117(15):1973). We have identified a new lysosomal sialidase Neu4 (J Biol Chem 2004 279:37021). We have generated a stable loss-of-function phenotype in cultured cells and in mice with targeted disruption of the Neu4 gene and showed that Neu4 is a functional component of the ganglioside-metabolizing system, contributing to the postnatal development of the brain and other vital organs (Hum Mol Genet 2008 17(11):1556).

3. Genomics and proteomics of human disease. We used proteomics-based technologies for the diagnostics and for the discovery of targets for treatment and prevention of human diseases. Our studies of proteomes of blood vessel cells helped to establish new signaling pathways for arterial vasculature (Circ Res 2002 91:915; FASEB J 2004 18:705) whereas functional proteomic study of the fat tissue defined a new major adipocyte lipase (J Biol Chem 2004 279:40683). We have compared proteomes of apical plasma membranes purified from proliferating human colorectal adenocarcinoma cells with those of the cells that spontaneously underwent an enterocytic differentiation which defined differential expression of more than 130 proteins and contributed to the understanding of the complexity of changes occurring during the differentiation of intestinal cells (Proteomics 2007 7:2201).

4. Development of new proteomic technology. We have developed a new technology for quantification of proteins in a proteome (#PCT/CA2004/001427). This method based on peptide labelling with stable isotopes provides an 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 (Rapid Commun Mass Spect 2007 21:2671).

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Current projects in the laboratory fall into four major areas:

1. Role of protein sialylation and sialidases/neuraminidases. We are trying to understand the role played by glycan chains containing a specific sugar, sialic (acetyl-neuraminic) acid in cell and protein recognition and regulation of metabolism and signaling. In particular we study genetically targeted mice with knock-out enzymes sialidases that remove sialic acid from the surface of proteins and lipids.

2. Molecular basis of lysosomal storage disorders. We study inherited metabolic disorders called lysosomal disorders characterized by accumulation of macromolecules in the lysosome. We cloned the genes mutated in lysosomal disorders sialidosis and mucopolysaccharidosis IIIC and study the biochemical effects of genetic mutations identified in patients.

3. Comparative proteomics and phosphoproteomics. We use a proteomics-based technology for the diagnostics and for the discovery of targets for treatment and prevention of human diseases, including type 2 diabetes mellitus. We also develop new technologies for quantification of proteins and phosphoproteins in a proteome.

4. Role of lysosomal cathepsins in regulation of vasoconstriction and elastogenesis. Using genetically targeted mice depleted from lysosomal peptidases (cathepsins) we study the role of these enzymes in catabolism of vasoactive and mitogenic peptides: endothelin 1 and angiotensis that play important role in hemodynamic functions, adaptation of vascular wall and remodelling of arteries after chemical and mechanical injuries.