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Transcript of Dublin How yeast can help us understand human genetic disorders (and other biological problems): the...
Dublin
How yeast can help us understand human genetic disorders (and other biological
problems): the case of
Classic Galactosemia
Claudio Akio MasudaYeast Biochemistry and Molecular Biology Lab
Instituto de Bioquímica Médica Leopoldo de Meis
Universidade Federal do Rio de Janeiro
February 2015
Yeast Biochemistry and Molecular Biology Lab
• Biomedicine:– Lithium– Classic Galactosemia (type I)– Lipid metabolism
• Biotechnology: – Alcoholic fermentation– Lipid metabolism/SCO
Strategy
– Perform a genetic screening in yeast.
– Characterize the role of genes/pathways identified on the screenings.
– Design ways to intervene with the biological process.
Haploid KO library ~ 6.000 mutantsGrowth in galactosemic conditions
UPR has a protective effect in yeast models of galactosemia
De-Souza, Pimentel, Machado et al, 2014De-Souza, Pimentel, Machado et al, 2014
UPR – unfolded protein response
New therapeutic strategy?
Can we target the UPR and/or ER stress to treat Classic Galactosemia?
New drug target candidate?
Gene X has a human homologue with 59% similarity and 43% identity in protein sequence
Other hits
• Phosphate homeostasis
• N-glycosylation
• Calcium homeostasis
• Calcium signalling
• MAPK
• Oxidative stress
• Etc…
Acknoledgements
• Genetics
• Biochemistry
• Molecular Biology
• Little bit of cell biology
What do we do?
Classic Galactosemia
• Human genetic disorder caused by deleterious mutations on the GALT gene which encodes galactose-1-phosphate uridyltransferase.
• Autossomic recessive (1:20.000 in Brazil)
• Symptoms include gastrointestinal problems, cataract formation, hepatosplenomegaly and bacterial sepsis in newborns that, if not treated properly, can lead to death.
• The only treatment is the implementation of a galactose/lactose-free diet.
• Galactose-1-phosphate accumulation is a hallmark of this disease.
Li+
Leloir pathway
gal7
Masuda et al., 2001
Summary of the results from the genetic screening
Galactokinase deletion abolishes galactose-1-phosphate accumulation
gal7
Masuda et al., 2001
Deletion of galactokinase protects from galactose toxicity
De-Souza, Pimentel, Machado et al, 2014
Galactokinase is a drug target candidate for the treatment of type I galactosemia
Copy and Paste
• Can we use the same strategy to address other biological problems?
• YES!
• We are already applying this same strategy to study lipid metabolism.