Skip to main content

Advertisement

SpringerLink
Log in

Cephalic Neuronal Vesicle Formation is Developmentally Dependent and Modified by Methylmercury and sti-1 in Caenorhabditis elegans

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Methylmercury (MeHg) is a potent neurotoxicant. The mechanisms underlying MeHg-induced neurotoxicity are not fully understood. Several studies have shown that protein chaperones are involved in MeHg toxicity. The protein co-chaperone, stress inducible protein 1 (STI-1), has important functions in protein quality control of the chaperone pathway. In the current study, dopaminergic (DAergic) cephalic (CEP) neuronal morphology was evaluated in the Caenorhabditis elegans (C. elegans) sti-1 knockout strain. In the control OH7193 strain (dat-1::mCherry + ttx-3::mCherry), we characterized the morphology of CEP neurons by checking the presence of attached vesicles and unattached vesicles to the CEP dendrites. We showed that the attached vesicles were only present in adult stage worms; whereas they were absent in the younger L3 stage worms. In the sti-1 knockout strain, MeHg treatment significantly altered the structures of CEP dendrites with discontinuation of mCherry fluorescence and shrinkage of CEP soma, as compared to the control. 12 h post treatment on MeHg-free OP50-seeded plates, the discontinuation of mCherry fluorescence of CEP dendrites in worms treated with 0.05 or 0.5 µM MeHg returned to levels statistically indistinguishable from control, while in worms treated with 5 µM MeHg a higher percentage of discontinuation of mCherry fluorescence persisted. Despite this strong effect by 5 µM MeHg, CEP attached vesicles were increased upon 0.05 or 0.5 µM MeHg treatment, yet unaffected by 5 µM MeHg. The CEP attached vesicles of sti-1 knockout strain were significantly increased shortly after MeHg treatment, but were unaffected 48 h post treatment. In addition, there was a significant interactive effect of MeHg and sti-1 on the number of attached vesicles. Knock down sti-1 via RNAi did not alter the number of CEP attached vesicles. Taking together, our data suggests that the increased occurrence of attached vesicles in adult stage worms could initiate a substantial loss of membrane components of CEP dendrites following release of vesicles, leading to the discontinuation of mCherry fluorescence, and the formation of CEP attached vesicles could be regulated by sti-1 to remove cellular debris for detoxification.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Hipp MS, Kasturi P, Hartl FU (2019) The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol 20:421–435

    Article  CAS  Google Scholar 

  2. Ciechanover A, Kwon YT (2017) Protein quality control by molecular chaperones in neurodegeneration. Front Neurosci 11:185

    Article  Google Scholar 

  3. Sontag EM, Samant RS, Frydman J (2017) Mechanisms and functions of spatial protein quality control. Annu Rev Biochem 86:97–122

    Article  CAS  Google Scholar 

  4. Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22

    Article  CAS  Google Scholar 

  5. Karagas MR, Choi AL, Oken E, Horvat M, Schoeny R, Kamai E, Cowell W, Grandjean P, Korrick S (2012) Evidence on the human health effects of low-level methylmercury exposure. Environ Health Perspect 120:799–806

    Article  CAS  Google Scholar 

  6. Caito S, Zeng H, Aschner JL, Aschner M (2014) Methylmercury alters the activities of Hsp90 client proteins, prostaglandin E synthase/p23 (PGES/23) and nNOS. PLoS ONE 9:e98161

    Article  Google Scholar 

  7. Aschner M, Aschner JL (1990) Mercury neurotoxicity: mechanisms of blood-brain barrier transport. Neurosci Biobehav Rev 14:169–176

    Article  CAS  Google Scholar 

  8. Ajsuvakova OP, Tinkov AA, Aschner M, Rocha JBT, Michalke B, Skalnaya MG, Skalny AV, Butnariu M, Dadar M, Sarac I, Aaseth J, Bjørklund G (2020) Sulfhydryl groups as targets of mercury toxicity. Coord Chem Rev 417:213343

    Article  CAS  Google Scholar 

  9. Nogara PA, Oliveira CS, Schmitz GL, Piquini PC, Farina M, Aschner M, Rocha JBT (2019) Methylmercury’s chemistry: from the environment to the mammalian brain. Biochim Biophys Acta Gen Subj 1863:129284

    Article  CAS  Google Scholar 

  10. Zou J, Guo Y, Guettouche T, Smith DF, Voellmy R (1998) Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94:471–480

    Article  CAS  Google Scholar 

  11. Morimoto RI (1993) Cells in stress: transcriptional activation of heat shock genes. Science 259:1409–1410

    Article  CAS  Google Scholar 

  12. Hashimoto-Torii K, Torii M, Fujimoto M, Nakai A, El Fatimy R, Mezger V, Ju MJ, Ishii S, Chao SH, Brennand KJ, Gage FH, Rakic P (2014) Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron 82:560–572

    Article  CAS  Google Scholar 

  13. Hwang GW, Ryoke K, Lee JY, Takahashi T, Naganuma A (2011) siRNA-mediated silencing of the gene for heat shock transcription factor 1 causes hypersensitivity to methylmercury in HEK293 cells. J Toxicol Sci 36:851–853

    Article  CAS  Google Scholar 

  14. Chang HC, Nathan DF, Lindquist S (1997) In vivo analysis of the Hsp90 cochaperone Sti1 (p60). Mol Cell Biol 17:318–325

    Article  CAS  Google Scholar 

  15. Odunuga OO, Longshaw VM, Blatch GL (2004) Hop: more than an Hsp70/Hsp90 adaptor protein. BioEssays 26:1058–1068

    Article  CAS  Google Scholar 

  16. Wegele H, Wandinger SK, Schmid AB, Reinstein J, Buchner J (2006) Substrate transfer from the chaperone Hsp70 to Hsp90. J Mol Biol 356:802–811

    Article  CAS  Google Scholar 

  17. Beraldo FH, Soares IN, Goncalves DF, Fan J, Thomas AA, Santos TG, Mohammad AH, Roffe M, Calder MD, Nikolova S, Hajj GN, Guimaraes AL, Massensini AR, Welch I, Betts DH, Gros R, Drangova M, Watson AJ, Bartha R, Prado VF, Martins VR, Prado MA (2013) Stress-inducible phosphoprotein 1 has unique cochaperone activity during development and regulates cellular response to ischemia via the prion protein. FASEB J 27:3594–3607

    Article  CAS  Google Scholar 

  18. Song HO, Lee W, An K, Lee HS, Cho JH, Park ZY, Ahnn J (2009) C. elegans STI-1, the homolog of Sti1/Hop, is involved in aging and stress response. J Mol Biol 390:604–617

    Article  CAS  Google Scholar 

  19. Ke T, Tsatsakis A, Santamaria A, Antunes Soare FA, Tinkov AA, Docea AO, Skalny A, Bowman AB, Aschner M (2020) Chronic exposure to methylmercury induces puncta formation in cephalic dopaminergic neurons in Caenorhabditis elegans. Neurotoxicology 77:105

    Article  CAS  Google Scholar 

  20. Xu F, Kula-Eversole E, Iwanaszko M, Hutchison AL, Dinner A, Allada R (2019) Circadian clocks function in concert with heat shock organizing protein to modulate mutant huntingtin aggregation and toxicity. Cell Rep 27:59–70 (e54)

    Article  CAS  Google Scholar 

  21. Masoudi N, Ibanez-Cruceyra P, Offenburger SL, Holmes A, Gartner A (2014) Tetraspanin (TSP-17) protects dopaminergic neurons against 6-OHDA-induced neurodegeneration in C. elegans. PLoS Genet 10:e1004767

    Article  Google Scholar 

  22. Melentijevic I, Toth ML, Arnold ML, Guasp RJ, Harinath G, Nguyen KC, Taub D, Parker JA, Neri C, Gabel CV, Hall DH, Driscoll M (2017) C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. Nature 542:367–371

    Article  CAS  Google Scholar 

  23. Ke T, Aschner MJN (2019) Bacteria affect Caenorhabditis elegans responses to MeHg toxicity. Neurotoxicology 75:129–135

    Article  CAS  Google Scholar 

  24. Kaganovich D, Kopito R, Frydman J (2008) Misfolded proteins partition between two distinct quality control compartments. Nature 454:1088–1095

    Article  CAS  Google Scholar 

  25. Schindler AJ, Baugh LR, Sherwood DR (2014) Identification of late larval stage developmental checkpoints in Caenorhabditis elegans regulated by insulin/IGF and steroid hormone signaling pathways. PLoS Genet 10:e1004426

    Article  Google Scholar 

  26. Ren P, Lim CS, Johnsen R, Albert PS, Pilgrim D, Riddle DL (1996) Control of C. elegans larval development by neuronal expression of a TGF-beta homolog. Science 274:1389–1391

    Article  CAS  Google Scholar 

  27. Bargmann CI, Horvitz HR (1991) Control of larval development by chemosensory neurons in Caenorhabditis elegans. Science 251:1243–1246

    Article  CAS  Google Scholar 

  28. Kim K, Sato K, Shibuya M, Zeiger DM, Butcher RA, Ragains JR, Clardy J, Touhara K, Sengupta P (2009) Two chemoreceptors mediate developmental effects of dauer pheromone in C. elegans. Science 326:994–998

    Article  CAS  Google Scholar 

  29. Schroeder NE, Androwski RJ, Rashid A, Lee H, Lee J, Barr MM (2013) Dauer-specific dendrite arborization in C. elegans is regulated by KPC-1/Furin. Curr Biol 23:1527–1535

    Article  CAS  Google Scholar 

  30. Limke TL, Heidemann SR, Atchison WD (2004) Disruption of intraneuronal divalent cation regulation by methylmercury: are specific targets involved in altered neuronal development and cytotoxicity in methylmercury poisoning? Neurotoxicology 25:741–760

    Article  CAS  Google Scholar 

  31. Marty MS, Atchison WD (1997) Pathways mediating Ca2+ entry in rat cerebellar granule cells following in vitro exposure to methyl mercury. Toxicol Appl Pharmacol 147:319–330

    Article  CAS  Google Scholar 

  32. Farina M, Aschner M, Rocha JB (2011) Oxidative stress in MeHg-induced neurotoxicity. Toxicol Appl Pharmacol 256:405–417

    Article  CAS  Google Scholar 

  33. Yin Z, Lee E, Ni M, Jiang H, Milatovic D, Rongzhu L, Farina M, Rocha JB, Aschner M (2011) Methylmercury-induced alterations in astrocyte functions are attenuated by ebselen. Neurotoxicology 32:291–299

    Article  CAS  Google Scholar 

  34. Yin Z, Milatovic D, Aschner JL, Syversen T, Rocha JB, Souza DO, Sidoryk M, Albrecht J, Aschner M (2007) Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes. Brain Res 1131:1–10

    Article  CAS  Google Scholar 

  35. Ma L, Li Y, Peng J, Wu D, Zhao X, Cui Y, Chen L, Yan X, Du Y, Yu L (2015) Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration. Cell Res 25:24–38

    Article  CAS  Google Scholar 

  36. Baindur-Hudson S, Edkins AL, Blatch GL (2015) Hsp70/Hsp90 organising protein (hop): beyond interactions with chaperones and prion proteins. Subcell Biochem 78:69–90

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health to MA (NIEHS R01ES007331 and R01ES010563). The authors thank the Analytical Imaging Facility (AIF) at Albert Einstein College of Medicine, which is sponsored by NCI cancer center support grant P30CA013330 and Shared Instrumentation Grant (SIG) 1S10OD023591-01. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).

Author information

Authors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Tao Ke & Michael Aschner

  2. Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Mexico City, 14269, Mexico

    Abel Santamaria

  3. Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Santa Maria, RS, Brazil

    Joao B. T. Rocha

  4. Yaroslavl State University, Sovetskaya St., 14, Yaroslavl, Russia, 150000

    Alex Tinkov

  5. IM Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia

    Alex Tinkov & Michael Aschner

  6. Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany

    Julia Bornhorst

  7. School of Health Sciences, Purdue University, West Lafayette, IN, 47907-2051, USA

    Aaron B. Bowman

  8. Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer Building, Room 209, Bronx, NY, 10461, USA

    Michael Aschner

Authors
  1. Tao Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abel Santamaria
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joao B. T. Rocha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alex Tinkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julia Bornhorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aaron B. Bowman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Aschner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Aschner.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ke, T., Santamaria, A., Rocha, J.B.T. et al. Cephalic Neuronal Vesicle Formation is Developmentally Dependent and Modified by Methylmercury and sti-1 in Caenorhabditis elegans. Neurochem Res 45, 2939–2948 (2020). https://doi.org/10.1007/s11064-020-03142-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-020-03142-8

Keywords

Search

Navigation