Academic Background
Ph. D. (1959) University of Birmingham (UK)
Yeast Molecular Genetics
The relationship between prion protein sequence and disease. Use of yeast as a model system for analysis of determinants of their transmembrane topology.
My laboratory uses yeast for the molecular genetic analysis of
determinants of transmembrane (TM) protein topology. Both prion diseases
and far more prevalent diseases such as Alzheimer's and cystic fibrosis result
from errors in folding, membrane insertion, localization or processing of TM
proteins. Although the topogenic signals that determine the topology of insertion
are quite well understood (and have been extensively studied in yeast by my lab),
the mechanisms for response to these signals are unknown. A long term goal is
to characterize these mechanisms by the analysis of yeast mutants defective in
responses to these signals. Our primary focus, however, is to use these techniques
to analyze the relationship between mutations in the mammalian prion protein (PrP),
membrane insertion and pathogenesis.
Misfolded forms of PrP appear to be both the infectious agent of prion
diseases and the primary cause of the neurotoxicity that leads to slowly
lethal destruction of the brain. About 10% of human prion disease are
familial, caused by mutations in the PrP gene. Recent studies show that,
in at least one class of such mutants, neurotoxicity correlates with increased
production of a normally rare transmembrane (TM) form of PrP, called
PrPCtm, that may be the actual toxic
form in all prion disease. We have shown that yeast is
an efficient system for analysis of the relationship between pathogenic
PrP mutations and TM topology. Using PrP as a model, we are collaborating
in analysis of a previously unidentified component of the mammalian protein
translocation apparatus that helps to control the topology of insertion of
PrP and, presumably, other translocated proteins.
