IA. Protein Folding in Infectious Disease and Cancer
IB. Protein Folding in Neurodegenerative Disease
II. Hsp 90: a Driver of Novelty in Evolution
III. Prions: Protein Elements of Genetic Diversity
Part IA: Protein Folding in Infectious Disease and Cancer
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|iBiology Archives: Susan Lindquist iBioSeminar (2008)|
In Part 1a, Dr. Lindquist explains the problem of protein folding. Proteins leave the ribosome as long, linear chains of amino acids but they need to fold into complex three dimensional shapes in the extremely crowded environment of the cytoplasm. Since protein misfolding can be disastrous for cells, proteins known as heat shock proteins (HSPs) have evolved to facilitate proper protein folding. Lindquist explains that sometimes the heat shock response becomes unbalanced resulting in human disease. In the case of cancer, HSPs help cancer cells survive many stresses that would typically kill them. In contrast, many neurodegenerative diseases are a result of protein misfolding and aggregation suggesting that, in these diseases, HSPs are not activated when they should be.
Yeast have many of the same cellular processes as humans including a stress response to aid in protein folding and prevent protein aggregation. In Part 1b, Lindquist describes how genetic screens in yeast helped scientists identify mutations that increased the formation of aggregates similar to those found in neurodegenerative diseases. Furthermore a screen in yeast of ~500,000 chemicals identified a number of compounds that prevented protein aggregation. Results from both experiments have since been validated in mice and human neuronal models.
When cells undergo stress, the expression of HSPs increases. In Part 2, Lindquist explains that while most HSPs are expressed only as needed, Hsp90 is expressed in excess. This “buffer” of Hsp90 facilitates the folding of some mutant proteins (such as v-src) that would usually misfold and be degraded by the cell. Thus, Hsp90 potentiates the impact of these mutations. Interestingly, the Hsp90 “buffer” can also act to hide or suppress the impact of other mutations. These “hidden” mutations are found when cells are stressed reducing the pool of available Hsp90. Thus, Hsp90 provides a plausible mechanism for allowing genetic diversity and fluctuating environments to fuel the pace of evolutionary change.
In her last talk, Lindquist focuses on prion proteins. Prions are perhaps best known as the infectious agents in diseases such as mad cow disease. However, Lindquist argues that there are many great things about prions too. They provide a protein-based mechanism of inheritance that allows organisms to develop new traits, quickly and reversibly, and thereby adapt to new environments. Working in yeast, Lindquist and her colleagues were able to identify numerous prion-like proteins that are induced at different levels, depending on the temperature, pH or presence of bacteria. Expression of prions caused heritable, phenotypic changes in the yeast demonstrating that prions are another mechanism by which environmental changes can induce new traits that can be passed onto progeny.
Susan Lindquist was a member and former Director of the Whitehead Institute for Biomedical Research. She was also a Howard Hughes Medical Institute Investigator and Professor of Biology at the Massachusetts Institute of Technology. She received her Ph.D. in biology from Harvard and was a postdoctoral fellow of the American Cancer Society. Lindquist was on the faculty of the University of Chicago for over 20 years before moving to MIT in 2001.
A pioneer in the study of protein folding, Lindquist 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 and she demonstrated that Hsp90 and prions each provide distinct but feasible mechanisms of Lamarckian inheritance.
Dr. Lindquist was an elected member of the National Academy of Sciences, the Academy of Medicine and the Royal Society. Her honors also included the Dickson Prize in Medicine, the Otto-Warburg Prize, the Genetics Society of America Medal, the FASEB Excellence in Science Award, the E.B. Wilson Medal, the Vanderbilt Prize for Women’s Excellence in Science and Mentorship and the National Medal of Science. Learn more about Susan Lindquist's research here.
Dr. Lindquist was a great scientist and a long time supporter of iBiology and we were deeply saddened to learn of her untimely death from cancer in October 2016.
- C. David Allis iBioSeminar: Epigenetics: Why Your DNA is Not Enough
- Arthur Horwich iBioSeminar: Chaperone-Assisted Protein Folding
- Arthur Horwich iBioMagazine: The Discovery of Chaperonin Assisted Protein Folding
- Susan Lindquist iBioEducation: Protein Folding and Disease
- Peter Walter iBioMagazine: Discovery Talk: Unfolding the Unfolded Protein Response
Brevis BJ. 2017. Susan Lindquist: Visionary Scientist and Peerless Mentor. J Cell Biol 216 (1) http://jcb.rupress.org/
Scherz-Shouval R, Santagata S, Mendillo M, Sholl LM, Ben-Aharon I, Beck AH, Dias-Santagata D, Koeva M, Stemmer SM, Whitesell L, Lindquist S, 2014. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell, 158(3): 564–578.
Dai C, Whitesell L, Rogers AB, Lindquist S, 2007. Heat-shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130: 1005-18.
Whitesell L, Lindquist S, 2009. Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert Opinion on Therapeutic Targets 13: 469-478.
Whitesell L, Lindquist SL, 2005. Hsp90 and the Chaperoning of Cancer. Nat Rev Cancer 5: 761-72.
Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR, Soldner F, Baru V, Lou Y, Freyzon Y, Cho S, Mungenast AE, Muffat J, Mitalipova M, Pluth MD, Jui, NT, Schule B, Lippard SJ, Tsai L-H, Krainc D, Buchwald SL, Jaenisch R and Lindquist S, 2013. Identification and rescue of α-synuclein toxicity in Parkinson patient–derived neurons. Science, 342(6161): 983-987.
Treusch S, Hamamichi S, Goodman JL, Matlack KES, Chung CY, Baru V, Shulman JM, Parrado A, Bevis BJ, Valastyan JS, Han H, Lindhagen-Persson M, Reiman EM, Evans DA, Bennett DA, Olofsson A, DeJager PL, Tanzi RE, Caldwell KA, Caldwell GA, Lindquist S, 2011. Functional links between Aβ toxicity, endocytic trafficking and Alzheimer’s Disease risk factors in yeast. Science 334(6060): 1241-5.
Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, et al., 2006. a-Synuclein Blocks ER-Golgi Traffic and Rab 1 Rescues Neuron Loss in Parkinson’s Models. Science 313: 324-28.
Khurana V, Tardiff D, Chung CY, Lindquist S, 2015. Toward stem cell-based phenotypic screens for neurodegenerative diseases. Nat Rev Neurol, 11: 339–50.
Khurana V, Lindquist S, 2010. Modelling neurodegeneration in Saccharomyces cerevisiae: why cook with baker's yeast? Nat Rev Neurosci 11: 436-49.
Rohner N, Jarosz DF, Kowalko JE, Yoshizawa M, Jeffery WR, Borowsky RL, Lindquist S, Tabin CJ, 2013. Cryptic variation in morphological evolution: HSP90 as a capacitor for loss of eyes in cavefish. Science, 342(6164): 1372-1375.
Cowen LE, Singh SD, Köhler JR, Collins C, Zaas A, Schell W, Aziz H, Mylonakis E, Perfect JR, Whitesell L, Lindquist S, 2009. Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc Natl Acad Sci USA 106: 2818-23.
Rutherford SL, Lindquist S, 1998. Hsp90 as a capacitor for morphological evolution. Nature 396: 336-42.
Taipale M, Jarosz DF, Lindquist S, 2010. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11: 515-28.
Jarosz DF, Lindquist S, 2010. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330: 1820-4.
Jarosz DF, Brown JCS, Walker GA, Datta MS, Ung WL, Lancaster AK, Chang A, Newby GA, Weitz DA, Bisson LF, Lindquist S, 2014. Cross-kingdom chemical communication drives a heritable, mutually beneficial prion-based transformation of metabolism. Cell, 158(5), 1083–1093.
Alberti S, Halfmann R, King O, Kapila A, Lindquist S, 2009. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137: 146-158.
Newby GA, Lindquist S, 2013. Blessings in disguise: biological benefits of prion-like mechanisms. Trends Cell Biol 23(6): 251-9.
Halfmann R, Lindquist S, 2010. Epigenetics in the extreme: Prions and the inheritance of environmentally acquired traits. Science 330: 629-32.