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Microbiology: Current Research 2017 | Volume 1, Issue 2
allied
academies Joint Conference
GLOBAL APPLIED MICROBIOLOGY CONFERENCE
MICROBIAL & BIOCHEMICAL RESEARCH AND TECHNOLOGIES
&
October 18-19, 2017
Toronto, Canada
International Congress on
Statement of the Problem: Many (>30) genetic diseases
result from a single amino acid or small mutation which leaves
considerable residual activity but induces a degree of misfolding
of themutant proteinwhich targets it for endoplasmic reticulum
associated degradation (ERAD), resulting in the complete loss of
mutant protein activity. ERAD, rather than the mutation per se,
precipitates disease symptoms.
Methodology & Theoretical Orientation: Several pathogenic
bacterial protein subunit toxins have evolved to hijack ERAD
as a means for A subunit access to the cytosol where the
pathological effect becomes manifested. These toxins e.g.
cholera toxin, shiga toxin, use the same ER translocon as is used
in ERAD. Indeed the A subunit contains a C terminal sequence
which mimics an unfolded protein. Such toxins provide a
basis for the direct control of the ERAD translocon and hence
temporarily block ERAD to rescue the mutant protein and
ameliorate disease have inactivated the catalytic
A subunit activity and added a hydrophobic C terminal addition
to generate toxoids which reverse disease symptoms in cell and
animal models
Findings: Cholera toxin and shiga toxin with a 0, 9 or 18
polyleucine tail, were able to partially block ERAD of F508del
CFTR cystic fibrosis cells and G370S GCC Gaucher disease
cells and increase CFTR mediated chloride transport and GCC
glucocerobrosidase activity in these cells and their mouse
models without significant induction of ER stress.
Conclusion & Significance: These benign prokaryotic toxoids
represent a new means to treat a large number of inherited
diseases
Speaker Biography
Clifford Lingwood completed his PhD at the University of London in 1974, and Post-
doctoral studies at the Universities of Washington and Toronto. He has been a Full
Professor at the University of Toronto since 1997 and is a Senior Scientist within
the Molecular Medicine Program of the Research Institute at the Hospital for Sick
Children, Toronto. His research program is concerned with the biochemistry, chemistry,
metabolism and function of glycosphingolipids with a view to the therapy of diseases in
which they are involved. He has published more than 200 papers in reputed journals.
Clifford Lingwood
University of Toronto, Canada
Prokaryote remedy to genetic misfolding diseases: Inactivated bacterial subunit
toxoids block ER associated degradation of misfolded proteins to rescue the
phenotype