Susan Lindquist

Our work covers a broad range of topics, unified by two overarching questions: how do proteins find their correct folds, and what happens when they don’t? The amino acid sequence of a polypeptide ultimately determines its native conformation, but in the extraordinarily crowded macromolecular environment of living cells (~300 mg protein/mL), many proteins either fail to fold, or do not remain properly folded for long. Macromolecular crowding does, however, have its advantages. It allows proteins with low concentrations and inherently weak affinities to find each other and form complex transient assemblies, and yet to rapidly re-assort into other protein complexes as biological imperatives dictate. All organisms find themselves balanced between these opposing detrimental and beneficial effects of protein crowding. Indeed, this dilemma is as ancient as life, as we now know it. 

We investigate protein-folding problems through a combination of biochemistry, cell biology and genetics. Because these problems are universal, and the systems that solve them are so highly conserved, we move back and forth between simple and complex organisms. Not surprisingly, protein homeostasis has a profound influence on many aspects of human biology and medicine. As knowledge and technologies have advanced, our work has increasingly taken us in a translational direction. We have made significant advances in areas as diverse as neurodegeneration, cancer and infectious disease.

Prions & phenotypic change in natural environments. Prion formation and loss occur spontaneously, but their rates increase with stress. This provides a mechanism for the acquisition of heritable phenotypes in response to environmental changes. Non-prion cells are well adapted to environment 1, but are poorly adapted to environment 2. When the environment changes, stress-induced changes in protein homeostasis result in an increased frequency of prion appearance, [PRION+] cells, and consequently the exploration of new phenotypes. Some phenotypes revealed by prions provide a fitness advantage in environment 2, so that [PRION+] cells survive and proliferate. The occasional loss of prion states—a process that is also increased by stress—ensures that non-prion cells will be available when conditions return to normal (environment 1). Figure adapted from Halfmann and Lindquist, 2010.

The Heat-Shock Response

The heat-shock response (HSR) is an ancient mechanism that empowers organisms to survive many types of stress. Our recent work focuses on two areas: how does the response enable tumor initiation and progression and how might it prevent neurodegeneration? We are motivated not only by the truly fascinating biology of this response, but the belief that learning to control it will afford important therapeutic opportunities.

The protein chaperone Hsp90, a component of the HSR, is specialized to chaperone a distinct class of unstable substrates including a wide variety of signal transducers. The strong connection between environmental stress and protein homeostasis, particularly for Hsp90's client proteins, can change the effects of genetic variation and lead to the evolution of new traits.

The Biology of Prions and Amyloids

Prions are proteins that can acquire self-perpetuating changes in structure that alter protein function and cell phenotype. They represent an epigenetic mechanism of inheritance because the altered phenotype is passed from generation to generation through the heritable changes in protein structure, with no underlying changes in nucleic acids. We have shown by cell biological, genetic and biochemical data that this protein-only mechanism controls the inheritance of the yeast prion [PSI+] through its protein determinant, Sup35. When Sup35 converts to a prion it sequesters most translation-termination activity in the cell away from the ribosome. The ensuing read-through of stop codons creates diverse new phenotypes that depend, in a combinatorial fashion, upon the genetic variation that lies downstream of stop codons. [PSI+] has been conserved for at least 500 million years of evolution. We’ve suggested that this prion, and others, serve as beneficial “bet-hedging” mechanisms to enhance survival in fluctuating environments.

Biochemically and genetically tractable, yeast prions such as Sup35 offer a fulcrum point for the study of amyloids – a notoriously difficult subject. The ability of self-perpetuating amyloids to serve as elements of inheritance has broad implications. Functional amyloids are important in many aspects of human biology, including the maintenance of neuronal synapses, the formation of mitochondrial antiviral signaling complexes and the production of bacterial biofilms (the source of most human infection and a biological form particularly recalcitrant to treatment). And, oligomeric intermediates in yeast amyloid assembly have uncanny similarity to toxic conformational intermediates in Alzheimer's and other diseases.

Neurodegenerative protein folding diseases

Over the past several years we have pioneered the use of yeast cells as a model system for studying the initial, precipitating cellular pathologies involved in protein-misfolding diseases, particularly those of the central nervous system. The models we have created (for pathologies involving polyQ-expansion, TDP-43, a-synuclein, and Aβ toxicities) have proven to have direct and specific relevance to human pathologies. We employ yeast cells in unbiased genetic and chemical screens for modifiers of the toxicity of human disease proteins, move hits from these screens into whole organism neuronal models in collaboration with other investigators, and subsequently to mammalian primary neuronal cultures.

In collaboration with the laboratory of Rudolph Jaenisch we have begun to test findings from simpler systems in neurons that are derived from human iPS cells produced from the skin cells of human patients. Currently, there is not a single approved therapeutic intervention combating the initiating pathology in the devastating protein homeostasis diseases we are studying. Our ultimate goal is to develop personalized therapeutic interventions for these complex, multifactorial diseases that will complement other developing strategies, intervening at other steps.

Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S, 2012. Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature 482 (7385): 363-368.

Heinrich SU, Lindquist S, 2011. Protein-only mechanism induces self-perpetuating changes in the activity of neuronal Aplysia cytoplasmic polyadenylation element binding protein (CPEB). Proc Natl Acad Sci USA 108: 2999-3004.

Jarosz DF, Lindquist S, 2010. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330: 1820-24.

Dong J, Castro CE, Boyce MC, Lang MJ, Lindquist S, 2010. Optical Trapping with High Forces Reveals Unexpected Behaviors of Prion Fibrils. Nat Struct Mol Biol 17: 1422-30.

Su LJ, Auluck PK, Outeiro TF, Yeger-Lotem E, Kritzer JA, Tardiff DF, Strathearn KE, Liu F, Cao S, Hamamichi S, Hill KJ, Caldwell KA, Bell GW, Fraenkel E, Cooper AA, Caldwell GA, McCaffery JM, Rochet J-C, Lindquist S, 2010. Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson disease models. Dis Model Mech 3: 194-208.

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: 146-58.

Yeger-Lotem E, Riva L, Su LJ, Gitler AD, Cashikar A, King OD, Auluck PK, Geddie ML, Valastyan JS, Karger DR, Lindquist S, Fraenkel E, 2009. Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity. Nat Genet 41: 316-23.

Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet J-C, Lindquist S, 2009. ?-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 41: 308-15.

Tyedmers J, Madariaga ML, Lindquist S, 2008. Prion Switching in Response to Environmental Stress. PLoS Biol 6: e294.

Duennwald ML, Lindquist S, 2008. Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity. Genes Dev 22: 3308-19.

Dai C, Whitesell L, Rogers AB, Lindquist S, 2007. Heat-shock factor 1 is a Powerful Multifaceted Modifier of Carcinogenesis. Cell 130: 1005-18.

Tessier PM, Lindquist S, 2007. Prion recognition elements govern nucleation, strain specificity and species barriers. Nature 447: 556-61.

Halfmann R, Lindquist S, 2010. Epigenetics in the Extreme: Prions and the Inheritance of Environmentally Acquired Traits. Science 330: 629.

Khurana V, Lindquist S, 2010. Modelling neurodegeneration in Saccharomyces cerevisiae: why cook with baker's yeast? Nat Rev Neurosci 11: 436-49.

Whitesell L, Lindquist S, 2009. Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert Opinion on Therapeutic Targets 13: 469-78.