Alexey Pshezhetsky, PhD
Professor of Pediatrics and Biochemistry
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.
Selected Scientific Contributions
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).
Click here for PubMed listing
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.