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’ve found that activation of the heat-shock response is a double-edged sword in relation to deadly diseases: on the one hand, this response can prevent protein aggregation associated with degenerative diseases of aging. Given this, one might expect that manipulating an increase in the heat shock response would halt or reverse the accumulation of misfolded, aggregated proteins such as α-synuclein as seen in Parkinson’s Disease or Tau and Aβ as seen in Alzheimer’s Disease. However the heat shock response also acts to enhance survival under stressful conditions and regulates a multitude of growth responses. In this way it puts tissues at risk for cancer by enabling tumor cells to evolve invasive, drug-resistant phenotypes. Thus, cancer cells and infectious organisms are using their survival responses against us while our brains are, in some situations, failing to use their survival response to protect us. Based on these findings, 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. Recently, we’ve characterized another prion, [GAR+], which provides the ultimate example of Lamarckian inheritance. A chemical secreted by bacteria causes a heritable switch in yeast metabolism by inducing [GAR+]. This metabolic switch benefits bacteria and yeast alike. Therefore, we’ve suggested that prions 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 infections and a biological form particularly recalcitrant to treatment). Interestingly, oligomeric intermediates in yeast amyloid assembly have uncanny similarity to toxic conformational intermediates in Alzheimer's and other diseases.
Neurodegenerative protein folding diseases
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. Our a-synuclein model has been particularly successful; we identified a compound that alleviates disturbances in cellular processes in screens of compounds in the yeast a-synuclein model, validated this compound in neuronal cells derived from human iPS cells produced from the skin cells of human patients and, returning to yeast, used genetics to identify the target of this compound. Further, development of computational methods transposing molecular interactions across species allow the well-described yeast interactome to be placed in the context of human genome-scale networks. This provides a more coherent human gene network that allows us to uncover unique mechanisms of neurodegeneration, link numerous neurodegenerative disease risk factors to α-synuclein and uncover drug targets. Our success here strongly encourages us as we further develop our yeast models for other neurodegenerative diseases.
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.
Jarosz DF, Lancaster AK, Brown JCS, Lindquist S, 2014. An evolutionarily conserved prion-like element converts wild fungi from metabolic specialists to generalists. Cell, 158, 1072–1082.
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, 1083–1093.
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.
Taipale M, Tucker G, Peng J, Krykbaeva I, Lin ZY, Larsen B, Choi H, Berger B, Gingras AC, Lindquist S, 2014. A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell, 158: 434-448.
Tardiff DF, Jui NT, Khurana V, Tambe MA, Thompson ML, Chung CY, Kamadurai HB, Kim HT, Lancaster AK, Caldwell KA, Caldwell GA, Rochet J-C, Buchwald SL and Lindquist S, 2013. Yeast Reveal a “Druggable” Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science, 342(6161): 979-983.
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.
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.
Santagata S, Mendillo ML, Tang Y, Subramanian A, Perley CC, Roche SP, Wong B, Narayan R, Kwon H, Koeva M, Amon A, Golub TR, Porco JA Jr, Whitesell L, Lindquist S, 2013. Tight coordination of protein translation and heat shock factor 1 activation supports the anabolic malignant state. Science, 341:doi:10.1126/science.1238303.
Taipale M, Krykbaeva I, Koeva M, Kayatekin C, Westover KD, Karras GI, Lindquist S, 2012. Quantitative analysis of hsp90-client interactions reveals principles of substrate recognition. Cell 150(5): 987-1001.
Mendillo ML, Santagata S, Koeva M, Bell G, Hu R, Tamimi RM, Fraenkel E, Ince TA, Whitesell L, Lindquist S, 2012. HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell 150(3): 549–562.
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.
Jarosz DF, Lindquist S, 2010. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330: 1820-24.
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.
Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet J-C, Lindquist S, 2009. Alpha-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 41: 308-15.
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.
Khurana V, Tardiff D, Chung CY, Lindquist S, 2015. Toward stem cell-based phenotypic screens for neurodegenerative diseases. Nat Rev Neurol, 11: 339–50.
Narayan P, Ehsani S, Lindquist S, Combatting neurodegenerative disease with chemical probes and model systems, Nat Chem Bio, 10: 911-20.
Tardiff DF, Khurana V, Chung CY, Lindquist S, 2014. From yeast to patient neurons and back again: powerful new discovery platforms. Movement Disorders, 29(10): 1231-40.
Valastyan JS, Lindquist S, 2014. Protein folding disease mechanisms at a glance. DMM, 7(1):9-14.
Newby GA, Lindquist S, 2013. Blessings in disguise: biological benefits of prion-like mechanisms. TCB 23(6): 251-9.