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From Yeast to Humans: Leveraging New Approaches in Yeast to Accelerate Discovery of Therapeutic Targets for Synucleinopathies

  • Jeff S. Piotrowski
  • Daniel F. TardiffEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 2049)

Abstract

Neurodegenerative diseases (ND) represent a growing, global health crisis, one that lacks any disease-modifying therapeutic strategy. This critical need for new therapies must be met with an exhaustive approach to exploit all tools available. A yeast (Saccharomyces cerevisiae) model of α-synuclein toxicity—the protein causally linked to Parkinson’s disease and other synucleinopathies—offers a powerful approach that takes advantage of the unique offerings of this system: tractable genetics, robust high-throughput screening strategies, unparalleled data repositories, powerful computational tools, and extensive evolutionary conservation of fundamental biological pathways. These attributes have enabled genetic and small molecule screens that have revealed toxic phenotypes and drug targets that translate directly to patient-derived iPSC neurons. Extending these insights, recent advances in genetic network analyses have generated the first “humanized” α-synuclein network, which has identified druggable proteins and led to validation of the toxic phenotypes in patient-derived cells. Unbiased phenotypic small molecule screens can identify compounds targeting critical proteins within α-synuclein networks. While identification of direct drug targets for phenotypic screen hits represents a bottleneck, high-throughput chemical genetic methods provide a means to uncover cellular targets and pathways for large numbers of compounds in parallel. Taken together, the yeast α-synuclein model and associated tools can reveal insights into underlying cellular pathologies, lead molecules and their cognate targets, and strategies to translate mechanisms of toxicity and cytoprotection into complex neuronal systems.

Key words

Parkinson’s disease α-Synuclein Genetic modifier screen Phenotypic small molecule screens Target identification Chemical genetics 

Notes

Acknowledgments

We thank Vikram Khurana for reviewing the manuscript. This chapter was made possible through the innovations and fearless investigations of the late Susan Lindquist (1949–2016). We gratefully dedicate this chapter to her.

References

  1. 1.
    Kachroo AH, Laurent JM, Yellman CM, Meyer AG, Wilke CO, Marcotte EM (2015) Evolution. Systematic humanization of yeast genes reveals conserved functions and genetic modularity. Science 348(6237):921–925.  https://doi.org/10.1126/science.aaa0769CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Auluck PK, Caraveo G, Lindquist S (2010) alpha-Synuclein: membrane interactions and toxicity in Parkinson’s disease. Annu Rev Cell Dev Biol 26:211–233.  https://doi.org/10.1146/annurev.cellbio.042308.113313CrossRefPubMedGoogle Scholar
  3. 3.
    Outeiro TF, Lindquist S (2003) Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science 302(5651):1772–1775.  https://doi.org/10.1126/science.1090439CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Spira PJ, Sharpe DM, Halliday G, Cavanagh J, Nicholson GA (2001) Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann Neurol 49(3):313–319CrossRefGoogle Scholar
  5. 5.
    Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302(5646):841.  https://doi.org/10.1126/science.1090278CrossRefPubMedGoogle Scholar
  6. 6.
    Bartels T, Choi JG, Selkoe DJ (2011) alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477(7362):107–110.  https://doi.org/10.1038/nature10324CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT Jr (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci U S A 97(2):571–576CrossRefGoogle Scholar
  8. 8.
    Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A 106(31):13010–13015.  https://doi.org/10.1073/pnas.0903691106CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ (2003) Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein. Science 302(5651):1769–1772.  https://doi.org/10.1126/science.1090389CrossRefPubMedGoogle Scholar
  10. 10.
    Hunn BH, Cragg SJ, Bolam JP, Spillantini MG, Wade-Martins R (2015) Impaired intracellular trafficking defines early Parkinson’s disease. Trends Neurosci 38(3):178–188.  https://doi.org/10.1016/j.tins.2014.12.009CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Pozo Devoto VM, Falzone TL (2017) Mitochondrial dynamics in Parkinson’s disease: a role for alpha-synuclein? Dis Model Mech 10(9):1075–1087.  https://doi.org/10.1242/dmm.026294CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313(5785):324–328.  https://doi.org/10.1126/science.1129462CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yeger-Lotem E, Riva L, Su LJ, Gitler AD, Cashikar AG, 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(3):316–323.  https://doi.org/10.1038/ng.337CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet JC, Lindquist S (2009) Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 41(3):308–315.  https://doi.org/10.1038/ng.300CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Soper JH, Kehm V, Burd CG, Bankaitis VA, Lee VM (2011) Aggregation of alpha-synuclein in S. cerevisiae is associated with defects in endosomal trafficking and phospholipid biosynthesis. J Mol Neurosci 43(3):391–405.  https://doi.org/10.1007/s12031-010-9455-5CrossRefPubMedGoogle Scholar
  16. 16.
    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 JC, Lindquist S (2010) Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson’s disease models. Dis Model Mech 3(3–4):194–208.  https://doi.org/10.1242/dmm.004267CrossRefPubMedGoogle Scholar
  17. 17.
    Buttner S, Bitto A, Ring J, Augsten M, Zabrocki P, Eisenberg T, Jungwirth H, Hutter S, Carmona-Gutierrez D, Kroemer G, Winderickx J, Madeo F (2008) Functional mitochondria are required for alpha-synuclein toxicity in aging yeast. J Biol Chem 283(12):7554–7560.  https://doi.org/10.1074/jbc.M708477200CrossRefPubMedGoogle Scholar
  18. 18.
    Wang S, Zhang S, Liou LC, Ren Q, Zhang Z, Caldwell GA, Caldwell KA, Witt SN (2014) Phosphatidylethanolamine deficiency disrupts alpha-synuclein homeostasis in yeast and worm models of Parkinson disease. Proc Natl Acad Sci U S A 111(38):E3976–E3985.  https://doi.org/10.1073/pnas.1411694111CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zabrocki P, Bastiaens I, Delay C, Bammens T, Ghillebert R, Pellens K, De Virgilio C, Van Leuven F, Winderickx J (2008) Phosphorylation, lipid raft interaction and traffic of alpha-synuclein in a yeast model for Parkinson. Biochim Biophys Acta 1783(10):1767–1780.  https://doi.org/10.1016/j.bbamcr.2008.06.010CrossRefPubMedGoogle Scholar
  20. 20.
    Caraveo G, Auluck PK, Whitesell L, Chung CY, Baru V, Mosharov EV, Yan X, Ben-Johny M, Soste M, Picotti P, Kim H, Caldwell KA, Caldwell GA, Sulzer D, Yue DT, Lindquist S (2014) Calcineurin determines toxic versus beneficial responses to alpha-synuclein. Proc Natl Acad Sci U S A 111(34):E3544–E3552.  https://doi.org/10.1073/pnas.1413201111CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Buttner S, Faes L, Reichelt WN, Broeskamp F, Habernig L, Benke S, Kourtis N, Ruli D, Carmona-Gutierrez D, Eisenberg T, D'Hooge P, Ghillebert R, Franssens V, Harger A, Pieber TR, Freudenberger P, Kroemer G, Sigrist SJ, Winderickx J, Callewaert G, Tavernarakis N, Madeo F (2013) The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca(2+) levels to alpha-synuclein toxicity in Parkinson’s disease models. Cell Death Differ 20(3):465–477.  https://doi.org/10.1038/cdd.2012.142CrossRefPubMedGoogle Scholar
  22. 22.
    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 LH, Krainc D, Buchwald SL, Jaenisch R, Lindquist S (2013) Identification and rescue of alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342(6161):983–987.  https://doi.org/10.1126/science.1245296CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Khurana V, Peng J, Chung CY, Auluck PK, Fanning S, Tardiff DF, Bartels T, Koeva M, Eichhorn SW, Benyamini H, Lou Y, Nutter-Upham A, Baru V, Freyzon Y, Tuncbag N, Costanzo M, San Luis BJ, Schondorf DC, Barrasa MI, Ehsani S, Sanjana N, Zhong Q, Gasser T, Bartel DP, Vidal M, Deleidi M, Boone C, Fraenkel E, Berger B, Lindquist S (2017) Genome-scale networks link neurodegenerative disease genes to alpha-synuclein through specific molecular pathways. Cell Syst 4(2):157–170.e114.  https://doi.org/10.1016/j.cels.2016.12.011CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tardiff DF, Jui NT, Khurana V, Tambe MA, Thompson ML, Chung CY, Kamadurai HB, Kim HT, Lancaster AK, Caldwell KA, Caldwell GA, Rochet JC, Buchwald SL, Lindquist S (2013) Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates alpha-synuclein toxicity in neurons. Science 342(6161):979–983.  https://doi.org/10.1126/science.1245321CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Xiong Y, Dawson TM, Dawson VL (2017) Models of LRRK2-associated Parkinson’s disease. Adv Neurobiol 14:163–191.  https://doi.org/10.1007/978-3-319-49969-7_9CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Swinney DC, Anthony J (2011) How were new medicines discovered? Nat Rev Drug Discov 10(7):507–519.  https://doi.org/10.1038/nrd3480CrossRefPubMedGoogle Scholar
  27. 27.
    Vincent BM, Tardiff DF, Piotrowski J, Aron R, Lucas M, Chung CY, Bacherman H, Chen Y, Pires M, Doshi DB, Sadlish H, Raja WK, Solis E, Khurana V, Le Bourdonnec B, Scannevin RH, Rhodes KJ (2018) Inhibiting stearoyl-CoA desaturase ameliorates a-synuclein cytotoxicity. Cell Rep 25(10):2742–2754.e31CrossRefGoogle Scholar
  28. 28.
    Treusch S, Hamamichi S, Goodman JL, Matlack KE, 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 Abeta toxicity, endocytic trafficking, and Alzheimer’s disease risk factors in yeast. Science 334(6060):1241–1245.  https://doi.org/10.1126/science.1213210CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Gitler AD, Bevis BJ, Shorter J, Strathearn KE, Hamamichi S, Su LJ, Caldwell KA, Caldwell GA, Rochet JC, McCaffery JM, Barlowe C, Lindquist S (2008) The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci U S A 105(1):145–150.  https://doi.org/10.1073/pnas.0710685105CrossRefPubMedGoogle Scholar
  30. 30.
    Sancenon V, Lee SA, Patrick C, Griffith J, Paulino A, Outeiro TF, Reggiori F, Masliah E, Muchowski PJ (2012) Suppression of alpha-synuclein toxicity and vesicle trafficking defects by phosphorylation at S129 in yeast depends on genetic context. Hum Mol Genet 21(11):2432–2449.  https://doi.org/10.1093/hmg/dds058CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Soper JH, Roy S, Stieber A, Lee E, Wilson RB, Trojanowski JQ, Burd CG, Lee VM (2008) Alpha-synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae. Mol Biol Cell 19(3):1093–1103.  https://doi.org/10.1091/mbc.E07-08-0827CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Dhungel N, Eleuteri S, Li LB, Kramer NJ, Chartron JW, Spencer B, Kosberg K, Fields JA, Stafa K, Adame A, Lashuel H, Frydman J, Shen K, Masliah E, Gitler AD (2015) Parkinson’s disease genes VPS35 and EIF4G1 interact genetically and converge on alpha-synuclein. Neuron 85(1):76–87.  https://doi.org/10.1016/j.neuron.2014.11.027CrossRefGoogle Scholar
  33. 33.
    Volles MJ, Lansbury PT Jr (2007) Relationships between the sequence of alpha-synuclein and its membrane affinity, fibrillization propensity, and yeast toxicity. J Mol Biol 366(5):1510–1522.  https://doi.org/10.1016/j.jmb.2006.12.044CrossRefPubMedGoogle Scholar
  34. 34.
    Zondler L, Miller-Fleming L, Repici M, Goncalves S, Tenreiro S, Rosado-Ramos R, Betzer C, Straatman KR, Jensen PH, Giorgini F, Outeiro TF (2014) DJ-1 interactions with alpha-synuclein attenuate aggregation and cellular toxicity in models of Parkinson’s disease. Cell Death Dis 5:e1350.  https://doi.org/10.1038/cddis.2014.307CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Dixon C, Mathias N, Zweig RM, Davis DA, Gross DS (2005) Alpha-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast. Genetics 170(1):47–59.  https://doi.org/10.1534/genetics.104.035493CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Sharma N, Brandis KA, Herrera SK, Johnson BE, Vaidya T, Shrestha R, Debburman SK (2006) alpha-Synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress. J Mol Neurosci 28(2):161–178.  https://doi.org/10.1385/JMN:28:2:161CrossRefPubMedGoogle Scholar
  37. 37.
    Shahpasandzadeh H, Popova B, Kleinknecht A, Fraser PE, Outeiro TF, Braus GH (2014) Interplay between sumoylation and phosphorylation for protection against alpha-synuclein inclusions. J Biol Chem 289(45):31224–31240.  https://doi.org/10.1074/jbc.M114.559237CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Basso E, Antas P, Marijanovic Z, Goncalves S, Tenreiro S, Outeiro TF (2013) PLK2 modulates alpha-synuclein aggregation in yeast and mammalian cells. Mol Neurobiol 48(3):854–862.  https://doi.org/10.1007/s12035-013-8473-zCrossRefPubMedGoogle Scholar
  39. 39.
    Tenreiro S, Reimao-Pinto MM, Antas P, Rino J, Wawrzycka D, Macedo D, Rosado-Ramos R, Amen T, Waiss M, Magalhaes F, Gomes A, Santos CN, Kaganovich D, Outeiro TF (2014) Phosphorylation modulates clearance of alpha-synuclein inclusions in a yeast model of Parkinson’s disease. PLoS Genet 10(5):e1004302.  https://doi.org/10.1371/journal.pgen.1004302CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Tardiff DF, Tucci ML, Caldwell KA, Caldwell GA, Lindquist S (2012) Different 8-hydroxyquinolines protect models of TDP-43 protein, alpha-synuclein, and polyglutamine proteotoxicity through distinct mechanisms. J Biol Chem 287(6):4107–4120.  https://doi.org/10.1074/jbc.M111.308668CrossRefPubMedGoogle Scholar
  41. 41.
    Griffioen G, Duhamel H, Van Damme N, Pellens K, Zabrocki P, Pannecouque C, van Leuven F, Winderickx J, Wera S (2006) A yeast-based model of alpha-synucleinopathy identifies compounds with therapeutic potential. Biochim Biophys Acta 1762(3):312–318.  https://doi.org/10.1016/j.bbadis.2005.11.009CrossRefPubMedGoogle Scholar
  42. 42.
    Flower TR, Chesnokova LS, Froelich CA, Dixon C, Witt SN (2005) Heat shock prevents alpha-synuclein-induced apoptosis in a yeast model of Parkinson’s disease. J Mol Biol 351(5):1081–1100.  https://doi.org/10.1016/j.jmb.2005.06.060CrossRefGoogle Scholar
  43. 43.
    Ocampo A, Liu J, Barrientos A (2013) NAD+ salvage pathway proteins suppress proteotoxicity in yeast models of neurodegeneration by promoting the clearance of misfolded/oligomerized proteins. Hum Mol Genet 22(9):1699–1708.  https://doi.org/10.1093/hmg/ddt016CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Suresh SN, Chavalmane AK, Dj V, Yarreiphang H, Rai S, Paul A, Clement JP, Alladi PA, Manjithaya R (2017) A novel autophagy modulator 6-Bio ameliorates SNCA/alpha-synuclein toxicity. Autophagy 13(7):1221–1234.  https://doi.org/10.1080/15548627.2017.1302045CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Petroi D, Popova B, Taheri-Talesh N, Irniger S, Shahpasandzadeh H, Zweckstetter M, Outeiro TF, Braus GH (2012) Aggregate clearance of alpha-synuclein in Saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome. J Biol Chem 287(33):27567–27579.  https://doi.org/10.1074/jbc.M112.361865CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Sampaio-Marques B, Felgueiras C, Silva A, Rodrigues M, Tenreiro S, Franssens V, Reichert AS, Outeiro TF, Winderickx J, Ludovico P (2012) SNCA (alpha-synuclein)-induced toxicity in yeast cells is dependent on sirtuin 2 (Sir2)-mediated mitophagy. Autophagy 8(10):1494–1509.  https://doi.org/10.4161/auto.21275CrossRefPubMedGoogle Scholar
  47. 47.
    Buttner S, Habernig L, Broeskamp F, Ruli D, Vogtle FN, Vlachos M, Macchi F, Kuttner V, Carmona-Gutierrez D, Eisenberg T, Ring J, Markaki M, Taskin AA, Benke S, Ruckenstuhl C, Braun R, Van den Haute C, Bammens T, van der Perren A, Frohlich KU, Winderickx J, Kroemer G, Baekelandt V, Tavernarakis N, Kovacs GG, Dengjel J, Meisinger C, Sigrist SJ, Madeo F (2013) Endonuclease G mediates alpha-synuclein cytotoxicity during Parkinson’s disease. EMBO J 32(23):3041–3054.  https://doi.org/10.1038/emboj.2013.228CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ciaccioli G, Martins A, Rodrigues C, Vieira H, Calado P (2013) A powerful yeast model to investigate the synergistic interaction of alpha-synuclein and tau in neurodegeneration. PLoS One 8(2):e55848.  https://doi.org/10.1371/journal.pone.0055848CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zabrocki P, Pellens K, Vanhelmont T, Vandebroek T, Griffioen G, Wera S, Van Leuven F, Winderickx J (2005) Characterization of alpha-synuclein aggregation and synergistic toxicity with protein tau in yeast. FEBS J 272(6):1386–1400.  https://doi.org/10.1111/j.1742-4658.2005.04571.xCrossRefPubMedGoogle Scholar
  50. 50.
    Lewandowski NM, Ju S, Verbitsky M, Ross B, Geddie ML, Rockenstein E, Adame A, Muhammad A, Vonsattel JP, Ringe D, Cote L, Lindquist S, Masliah E, Petsko GA, Marder K, Clark LN, Small SA (2010) Polyamine pathway contributes to the pathogenesis of Parkinson disease. Proc Natl Acad Sci U S A 107(39):16970–16975.  https://doi.org/10.1073/pnas.1011751107CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Piotrowski JS, Li SC, Deshpande R, Simpkins SW, Nelson J, Yashiroda Y, Barber JM, Safizadeh H, Wilson E, Okada H, Gebre AA, Kubo K, Torres NP, LeBlanc MA, Andrusiak K, Okamoto R, Yoshimura M, DeRango-Adem E, van Leeuwen J, Shirahige K, Baryshnikova A, Brown GW, Hirano H, Costanzo M, Andrews B, Ohya Y, Osada H, Yoshida M, Myers CL, Boone C (2017) Functional annotation of chemical libraries across diverse biological processes. Nat Chem Biol 13(9):982–993.  https://doi.org/10.1038/nchembio.2436CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Liang J, Clark-Dixon C, Wang S, Flower TR, Williams-Hart T, Zweig R, Robinson LC, Tatchell K, Witt SN (2008) Novel suppressors of alpha-synuclein toxicity identified using yeast. Hum Mol Genet 17(23):3784–3795.  https://doi.org/10.1093/hmg/ddn276CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ho CH, Magtanong L, Barker SL, Gresham D, Nishimura S, Natarajan P, Koh JLY, Porter J, Gray CA, Andersen RJ, Giaever G, Nislow C, Andrews B, Botstein D, Graham TR, Yoshida M, Boone C (2009) A molecular barcoded yeast ORF library enables mode-of-action analysis of bioactive compounds. Nat Biotechnol 27(4):369–377.  https://doi.org/10.1038/nbt.1534CrossRefPubMedGoogle Scholar
  54. 54.
    Alexopoulou Z, Lang J, Perrett RM, Elschami M, Hurry ME, Kim HT, Mazaraki D, Szabo A, Kessler BM, Goldberg AL, Ansorge O, Fulga TA, Tofaris GK (2016) Deubiquitinase Usp8 regulates alpha-synuclein clearance and modifies its toxicity in Lewy body disease. Proc Natl Acad Sci U S A 113(32):E4688–E4697.  https://doi.org/10.1073/pnas.1523597113CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Tuncbag N, Braunstein A, Pagnani A, Huang SS, Chayes J, Borgs C, Zecchina R, Fraenkel E (2013) Simultaneous reconstruction of multiple signaling pathways via the prize-collecting steiner forest problem. J Comput Biol 20(2):124–136.  https://doi.org/10.1089/cmb.2012.0092CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Tofaris GK, Kim HT, Hourez R, Jung JW, Kim KP, Goldberg AL (2011) Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway. Proc Natl Acad Sci U S A 108(41):17004–17009.  https://doi.org/10.1073/pnas.1109356108CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Davies SE, Hallett PJ, Moens T, Smith G, Mangano E, Kim HT, Goldberg AL, Liu JL, Isacson O, Tofaris GK (2014) Enhanced ubiquitin-dependent degradation by Nedd4 protects against alpha-synuclein accumulation and toxicity in animal models of Parkinson’s disease. Neurobiol Dis 64:79–87.  https://doi.org/10.1016/j.nbd.2013.12.011CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Gregori-Puigjane E, Setola V, Hert J, Crews BA, Irwin JJ, Lounkine E, Marnett L, Roth BL, Shoichet BK (2012) Identifying mechanism-of-action targets for drugs and probes. Proc Natl Acad Sci U S A 109(28):11178–11183.  https://doi.org/10.1073/pnas.1204524109CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5(12):993–996.  https://doi.org/10.1038/nrd2199CrossRefPubMedGoogle Scholar
  60. 60.
    Eder J, Sedrani R, Wiesmann C (2014) The discovery of first-in-class drugs: origins and evolution. Nat Rev Drug Discov 13(8):577–587.  https://doi.org/10.1038/nrd4336CrossRefPubMedGoogle Scholar
  61. 61.
    Giaever G, Flaherty P, Kumm J, Proctor M, Nislow C, Jaramillo DF, Chu AM, Jordan MI, Arkin AP, Davis RW (2004) Chemogenomic profiling: identifying the functional interactions of small molecules in yeast. Proc Natl Acad Sci U S A 101(3):793–798.  https://doi.org/10.1073/pnas.0307490100CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Parsons AB, Lopez A, Givoni IE, Williams DE, Gray CA, Porter J, Chua G, Sopko R, Brost RL, Ho CH, Wang J, Ketela T, Brenner C, Brill JA, Fernandez GE, Lorenz TC, Payne GS, Ishihara S, Ohya Y, Andrews B, Hughes TR, Frey BJ, Graham TR, Andersen RJ, Boone C (2006) Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast. Cell 126(3):611–625.  https://doi.org/10.1016/j.cell.2006.06.040CrossRefPubMedGoogle Scholar
  63. 63.
    Douglas CM, D'Ippolito JA, Shei GJ, Meinz M, Onishi J, Marrinan JA, Li W, Abruzzo GK, Flattery A, Bartizal K, Mitchell A, Kurtz MB (1997) Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother 41(11):2471–2479CrossRefGoogle Scholar
  64. 64.
    Wride DA, Pourmand N, Bray WM, Kosarchuk JJ, Nisam SC, Quan TK, Berkeley RF, Katzman S, Hartzog GA, Dobkin CE, Scott Lokey R (2014) Confirmation of the cellular targets of benomyl and rapamycin using next-generation sequencing of resistant mutants in S. cerevisiae. Mol BioSyst 10(12):3179–3187.  https://doi.org/10.1039/c4mb00146jCrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Hoon S, St Onge RP, Giaever G, Nislow C (2008) Yeast chemical genomics and drug discovery: an update. Trends Pharmacol Sci 29(10):499–504.  https://doi.org/10.1016/j.tips.2008.07.006CrossRefPubMedGoogle Scholar
  66. 66.
    Andrusiak K, Piotrowski JS, Boone C (2012) Chemical-genomic profiling: systematic analysis of the cellular targets of bioactive molecules. Bioorg Med Chem 20(6):1952–1960.  https://doi.org/10.1016/j.bmc.2011.12.023CrossRefPubMedGoogle Scholar
  67. 67.
    Hoepfner D, Helliwell SB, Sadlish H, Schuierer S, Filipuzzi I, Brachat S, Bhullar B, Plikat U, Abraham Y, Altorfer M, Aust T, Baeriswyl L, Cerino R, Chang L, Estoppey D, Eichenberger J, Frederiksen M, Hartmann N, Hohendahl A, Knapp B, Krastel P, Melin N, Nigsch F, Oakeley EJ, Petitjean V, Petersen F, Riedl R, Schmitt EK, Staedtler F, Studer C, Tallarico JA, Wetzel S, Fishman MC, Porter JA, Movva NR (2014) High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions. Microbiol Res 169(2–3):107–120.  https://doi.org/10.1016/j.micres.2013.11.004CrossRefPubMedGoogle Scholar
  68. 68.
    Lee AY, St Onge RP, Proctor MJ, Wallace IM, Nile AH, Spagnuolo PA, Jitkova Y, Gronda M, Wu Y, Kim MK, Cheung-Ong K, Torres NP, Spear ED, Han MK, Schlecht U, Suresh S, Duby G, Heisler LE, Surendra A, Fung E, Urbanus ML, Gebbia M, Lissina E, Miranda M, Chiang JH, Aparicio AM, Zeghouf M, Davis RW, Cherfils J, Boutry M, Kaiser CA, Cummins CL, Trimble WS, Brown GW, Schimmer AD, Bankaitis VA, Nislow C, Bader GD, Giaever G (2014) Mapping the cellular response to small molecules using chemogenomic fitness signatures. Science 344(6180):208–211.  https://doi.org/10.1126/science.1250217CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Simpkins SW, Nelson J, Deshpande R, Li SC, Piotrowski JS, Wilson EH, Gebre AA, Okamoto R, Ohya Y, Osada H, Yoshida M, Boone C, Myers CL (2017) Large-scale interpretation of chemical-genetic interaction profiles using a genetic interaction network. PLOS Comput Biol.  https://doi.org/10.1371/journal.pcbi.1006532
  70. 70.
    Costanzo M, Baryshnikova A, Bellay J, Kim Y, Spear ED, Sevier CS, Ding H, Koh JL, Toufighi K, Mostafavi S, Prinz J, St Onge RP, VanderSluis B, Makhnevych T, Vizeacoumar FJ, Alizadeh S, Bahr S, Brost RL, Chen Y, Cokol M, Deshpande R, Li Z, Lin ZY, Liang W, Marback M, Paw J, San Luis BJ, Shuteriqi E, Tong AH, van Dyk N, Wallace IM, Whitney JA, Weirauch MT, Zhong G, Zhu H, Houry WA, Brudno M, Ragibizadeh S, Papp B, Pal C, Roth FP, Giaever G, Nislow C, Troyanskaya OG, Bussey H, Bader GD, Gingras AC, Morris QD, Kim PM, Kaiser CA, Myers CL, Andrews BJ, Boone C (2010) The genetic landscape of a cell. Science 327(5964):425–431.  https://doi.org/10.1126/science.1180823CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Dickinson Q, Bottoms S, Hinchman L, McIlwain S, Li S, Myers CL, Boone C, Coon JJ, Hebert A, Sato TK, Landick R, Piotrowski JS (2016) Mechanism of imidazolium ionic liquids toxicity in Saccharomyces cerevisiae and rational engineering of a tolerant, xylose-fermenting strain. Microb Cell Factories 15:17.  https://doi.org/10.1186/s12934-016-0417-7CrossRefGoogle Scholar
  72. 72.
    Piotrowski JS, Okada H, Lu F, Li SC, Hinchman L, Ranjan A, Smith DL, Higbee AJ, Ulbrich A, Coon JJ, Deshpande R, Bukhman YV, McIlwain S, Ong IM, Myers CL, Boone C, Landick R, Ralph J, Kabbage M, Ohya Y (2015) Plant-derived antifungal agent poacic acid targets beta-1,3-glucan. Proc Natl Acad Sci U S A 112(12):E1490–E1497.  https://doi.org/10.1073/pnas.1410400112CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Williams DE, Dalisay DS, Patrick BO, Matainaho T, Andrusiak K, Deshpande R, Myers CL, Piotrowski JS, Boone C, Yoshida M, Andersen RJ (2011) Padanamides A and B, highly modified linear tetrapeptides produced in culture by a Streptomyces sp. isolated from a marine sediment. Org Lett 13(15):3936–3939.  https://doi.org/10.1021/ol2014494CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Fung SY, Sofiyev V, Schneiderman J, Hirschfeld AF, Victor RE, Woods K, Piotrowski JS, Deshpande R, Li SC, de Voogd NJ, Myers CL, Boone C, Andersen RJ, Turvey SE (2014) Unbiased screening of marine sponge extracts for anti-inflammatory agents combined with chemical genomics identifies girolline as an inhibitor of protein synthesis. ACS Chem Biol 9(1):247–257.  https://doi.org/10.1021/cb400740cCrossRefPubMedGoogle Scholar
  75. 75.
    Wyche TP, Piotrowski JS, Hou Y, Braun D, Deshpande R, McIlwain S, Ong IM, Myers CL, Guzei IA, Westler WM, Andes DR, Bugni TS (2014) Forazoline A: marine-derived polyketide with antifungal in vivo efficacy. Angew Chem Int Ed Engl 53(43):11583–11586.  https://doi.org/10.1002/anie.201405990CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Nelson J, Simpkins SW, Safizadeh H, Li S, Piotrowski J, Hirano H, Yashiroda Y, Osada H, Yoshida M, Boone C, Myers CL (2018) MOSAIC: a chemical-genetic interaction data repository and web resource for exploring chemical modes of action. Bioinformatics 34(7):1251–1252CrossRefGoogle Scholar
  77. 77.
    Ho CH, Piotrowski J, Dixon SJ, Baryshnikova A, Costanzo M, Boone C (2011) Combining functional genomics and chemical biology to identify targets of bioactive compounds. Curr Opin Chem Biol 15(1):66–78.  https://doi.org/10.1016/j.cbpa.2010.10.023CrossRefPubMedGoogle Scholar
  78. 78.
    Huang Z, Chen K, Zhang J, Li Y, Wang H, Cui D, Tang J, Liu Y, Shi X, Li W, Liu D, Chen R, Sucgang RS, Pan X (2013) A functional variomics tool for discovering drug-resistance genes and drug targets. Cell Rep 3(2):577–585.  https://doi.org/10.1016/j.celrep.2013.01.019CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Agarwal AK, Rogers PD, Baerson SR, Jacob MR, Barker KS, Cleary JD, Walker LA, Nagle DG, Clark AM (2003) Genome-wide expression profiling of the response to polyene, pyrimidine, azole, and echinocandin antifungal agents in Saccharomyces cerevisiae. J Biol Chem 278(37):34998–35015.  https://doi.org/10.1074/jbc.M306291200CrossRefPubMedGoogle Scholar
  80. 80.
    dos Santos SC, Tenreiro S, Palma M, Becker J, Sa-Correia I (2009) Transcriptomic profiling of the Saccharomyces cerevisiae response to quinine reveals a glucose limitation response attributable to drug-induced inhibition of glucose uptake. Antimicrob Agents Chemother 53(12):5213–5223.  https://doi.org/10.1128/AAC.00794-09CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Teixeira MC, Fernandes AR, Mira NP, Becker JD, Sa-Correia I (2006) Early transcriptional response of Saccharomyces cerevisiae to stress imposed by the herbicide 2,4-dichlorophenoxyacetic acid. FEMS Yeast Res 6(2):230–248.  https://doi.org/10.1111/j.1567-1364.2006.00041.xCrossRefPubMedGoogle Scholar
  82. 82.
    Richards AL, Hebert AS, Ulbrich A, Bailey DJ, Coughlin EE, Westphall MS, Coon JJ (2015) One-hour proteome analysis in yeast. Nat Protoc 10(5):701–714.  https://doi.org/10.1038/nprot.2015.040CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Hoehamer CF, Cummings ED, Hilliard GM, Rogers PD (2010) Changes in the proteome of Candida albicans in response to azole, polyene, and echinocandin antifungal agents. Antimicrob Agents Chemother 54(5):1655–1664.  https://doi.org/10.1128/AAC.00756-09CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Lomenick B, Hao R, Jonai N, Chin RM, Aghajan M, Warburton S, Wang J, Wu RP, Gomez F, Loo JA, Wohlschlegel JA, Vondriska TM, Pelletier J, Herschman HR, Clardy J, Clarke CF, Huang J (2009) Target identification using drug affinity responsive target stability (DARTS). Proc Natl Acad Sci U S A 106(51):21984–21989.  https://doi.org/10.1073/pnas.0910040106CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Franken H, Mathieson T, Childs D, Sweetman GM, Werner T, Togel I, Doce C, Gade S, Bantscheff M, Drewes G, Reinhard FB, Huber W, Savitski MM (2015) Thermal proteome profiling for unbiased identification of direct and indirect drug targets using multiplexed quantitative mass spectrometry. Nat Protoc 10(10):1567–1593.  https://doi.org/10.1038/nprot.2015.101CrossRefPubMedGoogle Scholar
  86. 86.
    Iwaki A, Ohnuki S, Suga Y, Izawa S, Ohya Y (2013) Vanillin inhibits translation and induces messenger ribonucleoprotein (mRNP) granule formation in Saccharomyces cerevisiae: application and validation of high-content, image-based profiling. PLoS One 8(4):e61748.  https://doi.org/10.1371/journal.pone.0061748CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Ohnuki S, Kobayashi T, Ogawa H, Kozone I, Ueda JY, Takagi M, Shin-Ya K, Hirata D, Nogami S, Ohya Y (2012) Analysis of the biological activity of a novel 24-membered macrolide JBIR-19 in Saccharomyces cerevisiae by the morphological imaging program CalMorph. FEMS Yeast Res 12(3):293–304.  https://doi.org/10.1111/j.1567-1364.2011.00770.xCrossRefPubMedGoogle Scholar
  88. 88.
    Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rub U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466(7310):1069–1075.  https://doi.org/10.1038/nature09320CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Yumanity TherapeuticsCambridgeUSA

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