Abstract
Prions are infectious misfolded proteins that assemble into oligomers and large aggregates, and are associated with neurodegeneration. It is believed that the oligomers contribute to cytotoxicity, although genetic and environmental factors have also been shown to have additional roles. The study of the yeast prion [PSI +] has provided valuable insights into how prions form and why they are toxic. Our recent work suggests that SDS-resistant oligomers arise and remodel early during the prion formation process, and lysates containing these newly formed oligomers are infectious. Previous work shows that toxicity is associated with prion formation and this toxicity is exacerbated by deletion of the VPS5 gene. Here, we show that newly made oligomer formation and infectivity of vps5∆ lysates are similar to wild-type strains. However using green fluorescent protein fusions, we observe that the assembly of fluorescent cytoplasmic aggregates during prion formation is different in vps5∆ strains. Instead of large immobile aggregates, vps5∆ strains have an additional population of small mobile foci. We speculate that changes in the cellular milieu in vps5∆ strains may reduce the cell’s ability to efficiently recruit and sequester newly formed prion particles into central deposition sites, resulting in toxicity.
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References
Agrawal S, Berggren KL, Marks E, Fox JH (2017) Impact of high iron intake on cognition and neurodegeneration in humans and in animal models: a systematic review. Nutr Rev 75:456–470. doi:10.1093/nutrit/nux015
Allen KD, Wegrzyn RD, Chernova TA, Muller S, Newnam GP, Winslett PA, Wittich KB, Wilkinson KD, Chernoff YO (2005) Hsp70 chaperones as modulators of prion life cycle: novel effects of Ssa and Ssb on the Saccharomyces cerevisiae prion [PSI+]. Genetics 169:1227–1242
Arslan F, Hong JY, Kanneganti V, Park SK, Liebman SW (2015) Heterologous aggregates promote de novo prion appearance via more than one mechanism. PLoS Genet 11:e1004814
Bertram L, Tanzi RE (2005) The genetic epidemiology of neurodegenerative disease. J Clin Investig 115:1449–1457
Byrne LJ, Cole DJ, Cox BS, Ridout MS, Morgan BJ, Tuite MF (2009) The number and transmission of [PSI] prion seeds (Propagons) in the yeast Saccharomyces cerevisiae. PLoS One 4:e4670
Campdelacreu J (2014) Parkinson disease and Alzheimer disease: environmental risk factors. Neurologia 29:541–549
Chernoff YO, Derkach IL, Inge-Vechtomov SG (1993) Multicopy SUP35 gene induces de-novo appearance of psi-like factors in the yeast Saccharomyces cerevisiae. Curr Genet 24:268–270
Chernoff YO, Lindquist SL, Ono B, Inge-Vechtomov SG, Liebman SW (1995) Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science 268:880–884
Cox B, Tuite M (2017) The life of [PSI]. Curr Genet. doi:10.1007/s00294-017-0714-7
Dengjel J, Hoyer-Hansen M, Nielsen MO, Eisenberg T, Harder LM, Schandorff S, Farkas T, Kirkegaard T, Becker AC, Schroeder S et al (2012) Identification of autophagosome-associated proteins and regulators by quantitative proteomic analysis and genetic screens. Mol Cell Proteomics 11:M111-014035. doi:10.1074/mcp.M111.014035
Derkatch IL, Chernoff YO, Kushnirov VV, Inge-Vechtomov SG, Liebman SW (1996) Genesis and variability of [PSI] prion factors in Saccharomyces cerevisiae. Genetics 144:1375–1386
Derkatch IL, Bradley ME, Zhou P, Chernoff YO, Liebman SW (1997) Genetic and environmental factors affecting the de novo appearance of the [PSI+] prion in Saccharomyces cerevisiae. Genetics 147:507–519
Derkatch IL, Bradley ME, Hong JY, Liebman SW (2001) Prions affect the appearance of other prions: the story of [PIN(+)]. Cell 106:171–182
Douglas PM, Treusch S, Ren HY, Halfmann R, Duennwald ML, Lindquist S, Cyr DM (2008) Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc Natl Acad Sci USA 105:7206–7211
Du Z, Crow ET, Kang HS, Li L (2010) Distinct subregions of Swi1 manifest striking differences in prion transmission and SWI/SNF function. Mol Cell Biol 30:4644–4655
Eaglestone SS, Ruddock LW, Cox BS, Tuite MF (2000) Guanidine hydrochloride blocks a critical step in the propagation of the prion-like determinant [PSI(+)] of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 97:240–244
Ganusova EE, Ozolins LN, Bhagat S, Newnam GP, Wegrzyn RD, Sherman MY, Chernoff YO (2006) Modulation of prion formation, aggregation, and toxicity by the actin cytoskeleton in yeast. Mol Cell Biol 26:617–629
Gerson JE, Mudher A, Kayed R (2016) Potential mechanisms and implications for the formation of tau oligomeric strains. Crit Rev Biochem Mol Biol 51:482–496
Horazdovsky BF, Davies BA, Seaman MN, McLaughlin SA, Yoon S, Emr SD (1997) A sorting nexin-1 homologue, Vps5p, forms a complex with Vps17p and is required for recycling the vacuolar protein-sorting receptor. Mol Biol Cell 8:1529–1541
Huang P, Lian F, Wen Y, Guo C, Lin D (2013) Prion protein oligomer and its neurotoxicity. Acta Biochim Biophys Sin (Shanghai) 45:442–451
Kaganovich D, Kopito R, Frydman J (2008) Misfolded proteins partition between two distinct quality control compartments. Nature 454:1088–1095
Kato M, Wickner W (2003) Vam10p defines a Sec18p-independent step of priming that allows yeast vacuole tethering. Proc Natl Acad Sci USA 100:6398–6403
Kayed R, Lasagna-Reeves CA (2013) Molecular mechanisms of amyloid oligomers toxicity. J Alzheimers Dis 33(Suppl 1):S67–S78
Keefer KM, True HL (2016) Prion-associated toxicity is rescued by elimination of cotranslational chaperones. PLoS Genet 12:e1006431
Keefer KM, Stein KC, True HL (2017) Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae. Sci Rep 7:5853
King CY, Diaz-Avalos R (2004) Protein-only transmission of three yeast prion strains. Nature 428:319–323
Kryndushkin DS, Alexandrov IM, Ter-Avanesyan MD, Kushnirov VV (2003) Yeast [PSI+] prion aggregates are formed by small Sup35 polymers fragmented by Hsp104. J Biol Chem 278:49636–49643
Lancaster AK, Bardill JP, True HL, Masel J (2010) The spontaneous appearance rate of the yeast prion [PSI+] and its implications for the evolution of the evolvability properties of the [PSI+] system. Genetics 184:393–400
Liebman SW, Chernoff YO (2012) Prions in yeast. Genetics 191:1041–1072
Liu JJ, Lindquist S (1999) Oligopeptide-repeat expansions modulate ‘protein-only’ inheritance in yeast. Nature 400:573–576
Liu TT, Gomez TS, Sackey BK, Billadeau DD, Burd CG (2012) Rab GTPase regulation of retromer-mediated cargo export during endosome maturation. Mol Biol Cell 23:2505–2515
Lund PM, Cox BS (1981) Reversion analysis of [psi−] mutations in Saccharomyces cerevisiae. Genet Res 37:173–182
Manogaran AL, Hong JY, Hufana J, Tyedmers J, Lindquist S, Liebman SW (2011) Prion formation and polyglutamine aggregation are controlled by two classes of genes. PLoS Genet 7:e1001386
Mathur V, Taneja V, Sun Y, Liebman SW (2010) Analyzing the birth and propagation of two distinct prions, [PSI+] and [Het-s](y), in yeast. Mol Biol Cell 21:1449–1461
Ness F, Ferreira P, Cox BS, Tuite MF (2002) Guanidine hydrochloride inhibits the generation of prion “seeds” but not prion protein aggregation in yeast. Mol Cell Biol 22:5593–5605
Nothwehr SF, Hindes AE (1997) The yeast VPS5/GRD2 gene encodes a sorting nexin-1-like protein required for localizing membrane proteins to the late Golgi. J Cell Sci 110(Pt 9):1063–1072
Osherovich LZ, Weissman JS (2001) Multiple Gln/Asn-rich prion domains confer susceptibility to induction of the yeast [PSI(+)] prion. Cell 106:183–194
Patel BK, Liebman SW (2007) “Prion-proof” for [PIN+]: infection with in vitro-made amyloid aggregates of Rnq1p-(132-405) induces [PIN+]. J Mol Biol 365:773–782
Saarikangas J, Barral Y (2016) Protein aggregation as a mechanism of adaptive cellular responses. Curr Genet 62:711–724
Salahuddin P, Fatima MT, Abdelhameed AS, Nusrat S, Khan RH (2016) Structure of amyloid oligomers and their mechanisms of toxicities: targeting amyloid oligomers using novel therapeutic approaches. Eur J Med Chem 114:41–58
Salnikova AB, Kryndushkin DS, Smirnov VN, Kushnirov VV, Ter-Avanesyan MD (2005) Nonsense suppression in yeast cells overproducing Sup35 (eRF3) is caused by its non-heritable amyloids. J Biol Chem 280:8808–8812
Seaman MN, McCaffery JM, Emr SD (1998) A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast. J Cell Biol 142:665–681
Sharma J, Wisniewski BT, Paulson E, Obaoye JO, Merrill SJ, Manogaran AL (2017) De novo [PSI +] prion formation involves multiple pathways to form infectious oligomers. Sci Rep 7:76
Tanaka M, Chien P, Naber N, Cooke R, Weissman JS (2004) Conformational variations in an infectious protein determine prion strain differences. Nature 428:323–328
Tyedmers J, Madariaga ML, Lindquist S (2008) Prion switching in response to environmental stress. PLoS Biol 6:e294
Vishveshwara N, Bradley ME, Liebman SW (2009) Sequestration of essential proteins causes prion associated toxicity in yeast. Mol Microbiol 73:1101–1114
Wegrzyn RD, Bapat K, Newnam GP, Zink AD, Chernoff YO (2001) Mechanism of prion loss after Hsp104 inactivation in yeast. Mol Cell Biol 21:4656–4669
Zhou P, Derkatch IL, Liebman SW (2001) The relationship between visible intracellular aggregates that appear after overexpression of Sup35 and the yeast prion-like elements [PSI(+)] and [PIN(+)]. Mol Microbiol 39:37–46
Acknowledgements
We thank Susan Liebman for the gifts of plasmids and strains used in this study. The Sup35C (BE4) antibody was a gift from Viravan Prapapanich and Susan Liebman. We would also like to thank Jane Dorweiler, Doug Lyke, and Emily Davis for critical reading of the manuscript. This work was supported by a grant from the National Institutes of Health (GM109336) to A. L. M., and B. T. W. and E. R. L. were supported by the Marquette University Honors Research Fellowship.
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Communicated by M. Kupiec.
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Wisniewski, B.T., Sharma, J., Legan, E.R. et al. Toxicity and infectivity: insights from de novo prion formation. Curr Genet 64, 117–123 (2018). https://doi.org/10.1007/s00294-017-0736-1
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DOI: https://doi.org/10.1007/s00294-017-0736-1