Skip to main content
SpringerLink
Log in

Propofol Attenuates α-Synuclein Aggregation and Neuronal Damage in a Mouse Model of Ischemic Stroke

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

α-Synuclein is a soluble monomer abundant in the central nervous system. Aggregates of α-synuclein, consisting of higher-level oligomers and insoluble fibrils, have been observed in many chronic neurological diseases and are implicated in neurotoxicity and neurodegeneration. α-Synuclein has recently been shown to aggregate following acute ischemic stroke, exacerbating neuronal damage. Propofol is an intravenous anesthetic that is commonly used during intravascular embolectomy following acute ischemic stroke. While propofol has demonstrated neuroprotective properties following brain injury, the mechanism of protection in the setting of ischemic stroke is unclear. In this study, propofol administration significantly reduced the neurotoxic aggregation of α-synuclein, decreased the infarct area, and attenuated the neurological deficits after ischemic stroke in a mouse model. We then demonstrated that the propofol-induced reduction of α-synuclein aggregation was associated with increased mammalian target of rapamycin/ribosomal protein S6 kinase beta-1 signaling pathway activity and reduction of the excessive autophagy occurring after acute ischemic stroke.

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

Similar content being viewed by others

References

  1. Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, et al. The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 1995, 14: 467–475.

    Article  CAS  Google Scholar 

  2. Chandra S, Chen X, Rizo J, Jahn R, Südhof TC. A broken alpha-helix in folded alpha-synuclein. J Biol Chem 2003, 278: 15313–15318.

    Article  CAS  Google Scholar 

  3. Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 2010, 329: 1663–1667.

    Article  Google Scholar 

  4. Diógenes MJ, Dias RB, Rombo DM, Vicente Miranda H, Maiolino F, Guerreiro P, et al. Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J Neurosci 2012, 34: 11750–11762.

    Article  Google Scholar 

  5. Wong YC, Krainc D. α-Synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med 2017, 23: 1–13.

    Article  CAS  Google Scholar 

  6. Bartels T, Choi JG, Selkoe DJ. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 2011, 477: 107–110.

    Article  CAS  Google Scholar 

  7. Pieri L, Madiona K, Bousset L, Melki R. α-Synuclein and Huntingtin exon 1 assemblies are toxic to the cells. Biophys J 2012, 102: 2894–2905.

    Article  CAS  Google Scholar 

  8. Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, et al. In vivo demonstration that α-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 2011, 108: 4194–4199.

    Article  CAS  Google Scholar 

  9. Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 2003, 37: 583–595.

    Article  CAS  Google Scholar 

  10. Bonini NM, Giasson BI. Snaring the function of alpha-synuclein. Cell 2005, 123: 359–361.

    Article  CAS  Google Scholar 

  11. Cremades N, Cohen SI, Deas E, Abramov AY, Chen AY, Orte A, et al. Direct observation of the interconversion of normal and toxic forms of alpha-synuclein. Cell 2012, 149: 1048–1059.

    Article  CAS  Google Scholar 

  12. Unal-Cevik I, Gursoy-Ozdemir Y, Yemisci M, Lule S, Gurer G, Can A, et al. Alpha-synuclein aggregation induced by brief ischemia negatively impacts neuronal survival in vivo: a study in [A30P]alpha-synuclein transgenic mouse. J Cereb Blood Flow Metab 2011, 31: 913–23.

    Article  CAS  Google Scholar 

  13. Kim T, Mehta SL, Kaimal B, Lyons K, Dempsey RJ, Vemuganti R. Poststroke induction of α-synuclein mediates ischemic brain damage. J Neurosci 2016, 36: 7055–7065.

    Article  CAS  Google Scholar 

  14. Ham PB, Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol 2017, 157: 92–116.

    Article  CAS  Google Scholar 

  15. Wang P, Shao BZ, Deng Z, Chen S, Yue Z, Miao CY. Autophagy in ischemic stroke. Prog Neurobiol 2018, 163–164: 98–117.

    Article  Google Scholar 

  16. Gelb AW, Bayona NA, Wilson JX, Cechetto DF. Propofol anesthesia compared to awake reduces infarct size in rats. Anesthesiology 2002, 96: 1183–1190.

    Article  CAS  Google Scholar 

  17. Zhang J, Xia Y, Xu Z, Deng X. Propofol suppressed hypoxia/reoxygenation-induced apoptosis in HBVSMC by regulation of the expression of Bcl-2, Bax, Caspase3, Kir6.1, and p-JNK. Oxid Med Cell Longev 2016, 2016: 1–11.

    Google Scholar 

  18. Song M, Yu SP, Mohamad O, Cao W, Wei ZZ, Gu X, et al. Optogenetic stimulation of glutamatergic neuronal activity in the striatum enhances neurogenesis in the subventricular zone of normal and stroke mice. Neurobiol Dis 2017, 98: 9–24.

    Article  CAS  Google Scholar 

  19. Wei ZZ, Zhang JY, Taylor TM, Gu X, Zhao Y, Wei L. Neuroprotective and regenerative roles of intranasal Wnt-3a administration after focal ischemic stroke in mice. J Cereb Blood Flow Metab 2017, 38: 404–421.

    Article  Google Scholar 

  20. Xiong B, Li A, Lou Y, Chen S, Long B, Peng J, et al. Precise cerebral vascular atlas in stereotaxic coordinates of whole mouse brain. Front Neuroanat 2017, 11: 128.

    Article  Google Scholar 

  21. Woodlee MT, Asseo-García AM, Zhao X, Liu SJ, Jones TA, Schallert T. Testing forelimb placing across the midline reveals distinct, lesion-dependent patterns of recovery in rats. Exp Neurol 2005, 191: 310–317.

    Article  Google Scholar 

  22. Feldmeyer D, Brecht M, Helmchen F, Petersen CC, Poulet JF, Staiger JF, et al. Barrel cortex function. Prog Neurobiol 2013, 103: 3–27.

    Article  Google Scholar 

  23. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 2016, 12: 1–222.

  24. Mizushima N, Yoshimori T. How to interpret LC3 immunoblotting. Autophagy 2007, 3: 542–545.

    Article  CAS  Google Scholar 

  25. Magalhaes J, Gegg ME, Migdalska-Richards A, Doherty MK, Whitfield PD, Schapira AH. Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease. Hum Mol Genet 2016, 25: 3432–3445.

    Article  CAS  Google Scholar 

  26. Gao S, Duan C, Gao G, Wang X, Yang H. Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling. Int J Biochem Cell Biol 2015, 64: 25–33.

    Article  CAS  Google Scholar 

  27. Button RW, Roberts SL, Willis TL, Hanemann CO, Luo S. Accumulation of autophagosomes confers cytotoxicity. J Biol Chem 2017, 292: 13599–13614.

    Article  CAS  Google Scholar 

  28. Bademosi AT, Steeves J, Karunanithi S, Zalucki OH, Gormal RS, Liu S, et al. Trapping of Syntaxin1a in presynaptic nanoclusters by a clinically relevant general anesthetic. Cell Rep 2018, 22: 427–440.

    Article  CAS  Google Scholar 

  29. Bendor JT, Logan TP, Edwards RH. The function of alpha-synuclein. Neuron 2013, 79: 1044–1066.

    Article  CAS  Google Scholar 

  30. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, et al. Propagation of pathological α-synuclein in marmoset brain. Acta Neuropathol Commun 2017, 5: 5–12.

    Article  Google Scholar 

  31. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, et al. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 2017, 93: 1015–1034.

    Article  CAS  Google Scholar 

  32. Grassi D, Howard S, Zhou M, Diaz-Perez N, Urban NT, Guerrero-Given D, et al. Identification of a highly neurotoxic alpha-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease. Proc Natl Acad Sci U S A 2018, 115: E2634–E2643.

    Article  CAS  Google Scholar 

  33. Binolfi A, Limatola A, Verzini S, Kosten J, Theillet F, Rose HM, et al. Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites. Nature Commun 2016, 7: 10251.

    Article  CAS  Google Scholar 

  34. Liu J, Wang X, Lu Y, Duan C, Gao G, Lu L, et al. Pink1 interacts with α-synuclein and abrogates α-synuclein-induced neurotoxicity by activating autophagy. Cell Death Dis 2017, 8: e3056.

    Article  CAS  Google Scholar 

  35. Zhao QD, Viswanadhapalli S, Williams P, Shi Q, Tan C, Yi X, et al. NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways. Circulation 2015, 131: 643–655.

    Article  CAS  Google Scholar 

  36. Fink AL. The aggregation and fibrillation of α-synuclein. Acc Chem Res 2006, 39: 628–634.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Mengyao Qu and Yushang Zao for surgical assistance with the mouse stroke model. This work was supported by the National Natural Science Foundation of China (81771139) and the Beijing Natural Science Foundation (7194270).

Author information

Author notes

  1. Yuzhu Wang and Dan Tian have contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China

    Yuzhu Wang, Changwei Wei, Anshi Wu & Yun Yue

  2. Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

    Yuzhu Wang, Dan Tian, Huan Wang & Yanbing Zhu

  3. Washington University School of Medicine, St. Louis, MI, USA

    Victoria Cui

Authors
  1. Yuzhu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dan Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Changwei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Victoria Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanbing Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anshi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yun Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Anshi Wu or Yun Yue.

Ethics declarations

Conflict of interest

All authors claim that there are no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 57 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Tian, D., Wei, C. et al. Propofol Attenuates α-Synuclein Aggregation and Neuronal Damage in a Mouse Model of Ischemic Stroke. Neurosci. Bull. 36, 289–298 (2020). https://doi.org/10.1007/s12264-019-00426-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-019-00426-0

Keywords

Search

Navigation