I. Protein Folding and Prions
II. Prions and Evolution
Part II: Prions and Evolution
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What do "mad cows", people with neurodegenerative diseases and yeast cells growing happily on a deadly antibiotic have in common? They are all experiencing the consequences of misfolded proteins. Each organism has thousands of different proteins, which define its nature. Like origami paper, they can take the right path and fold into a swan or take the wrong path and fold into a rapacious hawk. The consequences can be deadly, leading to devastating neurodegenerative diseases in humans. Remarkably, a very similar folding process has been discovered in yeast, where it does no harm and can be studied easily and inexpensively.
Part II: In the case of the yeast prion [PSI], the misfolding of the Sup35 protein results in a simple change in metabolism. When misfolded Sup35 is passed from mother cells to their daughters, this metabolic change is inherited. This unusual genetic mechanism changes the organism in a heritable way due to a self-perpetuating change in protein conformation with no change in its DNA. The mechanism of epigenetic inheritance we have delineated provides a one-step process for the acquisition of complex traits and affords a route to the genetic assimilation of unstable traits that are not yet encoded in the genome.
Susan Lindquist is a member and former Director of the Whitehead Institute for Biomedical Research, which she guided as the Whitehead Genome Center was transformed into the neighboring Broad Institute.
She is also a Howard Hughes Medical Institute Investigator and Professor of Biology at Massachusetts Institute of Technology. She received her Ph.D. in biology from Harvard and was a postdoctoral fellow of the American Cancer Society. She was named the Albert D. Lasker Professor of Medical Sciences in 1999 at the University of Chicago. A pioneer in the study of protein folding, she established that protein homeostasis has profound and completely unexpected effects on normal biology and disease.
She found that the chaperone Hsp90 potentiates and buffers the effects of genetic variation, fueling evolutionary mechanisms as diverse as malignant transformation and the emergence of drug resistance. Her work established the molecular basis for protein-based mechanisms of inheritance. More recently she has built tractable genetic models of complex protein misfolding diseases, including Parkinson’s and Huntington’s diseases, which are providing new insights on the underlying pathogenic mechanisms.
Dr. Lindquist is an elected member of the National Academy of Sciences and the Institute of Medicine. Her honors also include the Dickson Prize in Medicine, Sigma Xi William Procter Prize for Scientific Achievement, Centennial Medal of the Harvard University Graduate School of Arts and Sciences, Otto-Warburg Prize, Genetics Society of America Medal, and FASEB Excellence in Science Award.
- Arthur Horwich iBioSeminar: Chaperone-Assisted Protein Folding
- Susan Lindquist iBioEducation: Protein Folding and Disease
- Peter Walter iBioMagazine: Unfolding the Unfolded Protein Response
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