Professor, Dept. of Pediatrics and Biochemistry, University of Montreal
Researcher, Dept. of Medical Genetics, Ste-Justine Hospital Research Center
H3T 1C5, Montreal, QC, Canada
tel 514-345-4931 ext 2736
Lysosomes are cytoplasmic organelles harbouring over 100 hydrolytic enzymes involved in the degradation of essentially all types of biological macromolecules. Any failure in the biogenesis, lysosomal targeting, supramolecular organization or function of one or more lysosomal enzymes can result in the progressive metabolic diseases called lysosomal storage diseases because of the massive accumulation of the undegraded substrates of the deficient enzymes in the lysosomes of the affected tissues. Dr. Pshezhetsky’s research aims on discovering the genes mutated in lysosomal diseases, identifying the molecular and biochemical defects in patients and developing therapies with a special emphasis on diseases caused by the deficiencies of lysosomal sialidases (sialidosis, galactosialidosis) and N-acetyltransferases (mucopolysaccharidosis IIIC).
Sialic acids are abundantly expressed on the cell surface and implicated in mediating recognition between the cells, between the cells and extracellular matrix as well as between the cells and a range of pathogenic viruses, bacteria and protozoa during the inflammatory and immune reactions. Much less is known about the role of sialidases (also called neuraminidases) and sialotransferases that can regulate cellular affinity by modifying the sialylation of cell surface molecules. Using the genetically targeted mouse models the team of Dr. Pshezhetsky is studying the role of neuraminidase 1 (Neu1) in signalling during the immune response, phagocytosis and glucose uptake, as well as the role of neuraminidase 4 (Neu4) in brain development.
Short vasoactive peptides are recognized as potent regulators of blood circulation. Through their interaction with different cell surface receptors, peptides can modulate blood pressure by such diverse mechanisms as contracting vascular smooth muscles, increasing or decreasing plasma volume, or by induction or suppression of vascular wall remodelling. Therefore, proteases involved in the catabolic proteolysis of circulating vasoactive peptides, which regulates their functional longevity and availability, play an important role in the regulation of vascular resistance. Using the knock-out mouse model the laboratory of Dr. Pshezhetsky studies the input of the major lysosomal serine carboxypeptidase A (cathepsin A) in post-translational processing of vasoactive peptides including angiotensin and endothelin.
Phosphorylation is the most frequent and important post-translational modification of proteins. Despite intensive research dedicated to the development of methods for the analysis of a phosphoproteome, identification of low-abundant cellular phosphoproteins still remains challenging, highlighting the need for novel techniques. The team of Dr. Pshezhetsky is involved in the development of new technologies for the global analysis and quantitative analysis of a phosphoproteome based on affinity resins for isolation of phosphopeptides and phosphoproteins and isotopic peptide tags. This technology should allow comparison of phosphoproteomes tracing up- and down-regulation of the individual proteins in order to identify novel drug targets and pharmacologically relevant metabolic and signaling pathways.