Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson’s Disease

Abstract

The accumulation of misfolded α-synuclein in dopamine (DA) neurons is believed to be of major importance in the pathogenesis of Parkinson’s disease (PD). Animal models of PD, based on viral-vector-mediated over-expression of α-synuclein, have been developed and show evidence of dopaminergic toxicity, providing us a good tool to investigate potential therapies to interfere with α-synuclein-mediated pathology. An efficient disease-modifying therapeutic molecule should be able to interfere with the neurotoxicity of α-synuclein aggregation. Our study highlighted the ability of an autophagy enhancer, trehalose (at concentrations of 5 and 2 % in drinking water), to protect against A53T α-synuclein-mediated DA degeneration in an adeno-associated virus serotype 1/2 (AAV1/2)-based rat model of PD. Behavioral tests and neurochemical analysis demonstrated a significant attenuation in α-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration including impaired DA neuronal survival and DA turnover, as well as α-synuclein accumulation and aggregation in the nigrostriatal system by commencing 5 and 2 % trehalose at the same time as delivery of AAV. Trehalose (0.5 %) was ineffective on the above behavioral and neurochemical deficits. Further investigation showed that trehalose enhanced autophagy in the striatum by increasing formation of LC3-II. This study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse α-synuclein aggregation for the treatment of PD.

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References

  1. 1.

    Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Siderowf A, Stern M (2003) Update on Parkinson disease. Ann Intern Med 138:651–658

    Article  PubMed  Google Scholar 

  3. 3.

    Iwatsubo T (2003) Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol 250(Suppl 3):III11–III14

    PubMed  Google Scholar 

  4. 4.

    Cole NB, Murphy DD, Lebowitz J, Di Noto L, Levine RL, Nussbaum RL (2005) Metal-catalyzed oxidation of alpha-synuclein: helping to define the relationship between oligomers, protofibrils, and filaments. J Biol Chem 280:9678–9690

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Chiba-Falek O, Lopez GJ, Nussbaum RL (2006) Levels of alpha-synuclein mRNA in sporadic Parkinson disease patients. Mov Disord 21:1703–1708

    Article  PubMed  Google Scholar 

  6. 6.

    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T et al (2003) Hardy JGwinn-Hardy K: alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Song W, Patel A, Qureshi HY, Han D, Schipper HM, Paudel HK (2009) The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells. J Neurochem 110:719–733

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Banerjee R, Beal MF, Thomas B (2010) Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci 33:541–549

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6:304–312

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11:1107–1117

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Jain NK, Roy I (2009) Effect of trehalose on protein structure. Protein Sci 18:24–36

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Richards AB, Krakowka S, Dexter LB, Schmid H, Wolterbeek AP, Waalkens-Berendsen DH, Shigoyuki A, Kurimoto M (2002) Trehalose: a review of properties, history of use and human tolerance, and results of multiple safety studies. Food Chem Toxicol 40:871–898

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Emanuele E (2014) Can trehalose prevent neurodegeneration? Insights from experimental studies. Curr Drug Targets 15:551–557

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC (2007) Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 282:5641–5652

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Wolkers WF, Walker NJ, Tablin F, Crowe JH (2001) Human platelets loaded with trehalose survive freeze-drying. Cryobiology 42:79–87

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Löw K, Aebischer P (2012) Use of viral vectors to create animal models for Parkinson’s disease. Neurobiol Dis 48:189–201

    Article  PubMed  Google Scholar 

  19. 19.

    Koprich JB, Johnston TH, Huot P, Reyes MG, Espinosa M, Brotchie JM (2011) Progressive neurodegeneration or endogenous compensation in an animal model of Parkinson’s disease produced by decreasing doses of alpha-synuclein. PLoS One 6:e17698

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Koprich JB, Johnston TH, Reyes MG, Sun X, Brotchie JM (2010) Expression of human A53T alpha-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson’s disease. Mol Neurodegener 5:43

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y et al (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19:5720–5728

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Sarkar S, Perlstein EO, Imarisio S, Pineau S, Cordenier A, Maglathlin RL, Webster JA, Lewis TA et al (2007) Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat Chem Biol 3:331–338

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15:1101–1111

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Tanida I, Ueno T, Kominami E (2004) LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 36:2503–2518

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118:2190–2199

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Casarejos MJ, Solano RM, Gomez A, Perucho J, de Yebenes JG, Mena MA (2011) The accumulation of neurotoxic proteins, induced by proteasome inhibition, is reverted by trehalose, an enhancer of autophagy, in human neuroblastoma cells. Neurochem Int 58:512–520

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki MNukina N (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10:148–154

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler DT, Goedert M (2012) Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain 135:2169–2177

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Yu WB, Jiang T, Lan DM, Lu JH, Yue ZY, Wang J, Zhou P (2012) Trehalose inhibits fibrillation of A53T mutant alpha-synuclein and disaggregates existing fibrils. Arch Biochem Biophys 523:144–150

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Lan DM, Liu FT, Zhao J, Chen Y, Wu JJ, Ding ZT, Yue ZY, Ren HM et al (2012) Effect of trehalose on PC12 cells overexpressing wild-type or A53T mutant α-synuclein. Neurochem Res 37:2025–2032

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Sarkar S, Chigurupati S, Raymick J, Mann D, Bowyer JF, Schmitt T, Beger RD, Hanig JP et al (2014) Neuroprotective effect of the chemical chaperone, trehalose in a chronic MPTP-induced Parkinson’s disease mouse model. Neurotoxicology 44:250–262

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Chung CY, Koprich JB, Siddiqi H, Isacson O (2009) Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J Neurosci 29:3365–3373

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Minutoli L, Altavilla D, Bitto A, Polito F, Bellocco E, Lagana G, Fiumara T, Magazu S et al (2008) Trehalose: a biophysics approach to modulate the inflammatory response during endotoxic shock. Eur J Pharmacol 589:272–280

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Echigo R, Shimohata N, Karatsu K, Yano F, Kayasuga-Kariya Y, Fujisawa A, Ohto T, Kita Y et al (2012) Trehalose treatment suppresses inflammation, oxidative stress, and vasospasm induced by experimental subarachnoid hemorrhage. J Transl Med 10:80

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Li J, Roubeix C, Wang Y, Shi S, Liu G, Baudouin C, Chen W (2012) Therapeutic efficacy of trehalose eye drops for treatment of murine dry eye induced by an intelligently controlled environmental system. Mol Vis 18:317–329

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Wang YQ, Tu ZC, Xu XY, Li R, Qu WM, Urade Y, Huang ZL (2012) Acute administration of fluoxetine normalizes rapid eye movement sleep abnormality, but not depressive behaviors in olfactory bulbectomized rats. J Neurochem 120:314–324

    Article  PubMed  Google Scholar 

  38. 38.

    Hong ZY, Huang ZL, Qu WM, Eguchi N (2005) Orexin A promotes histamine, but not norepinephrine or serotonin, release in frontal cortex of mice. Acta Pharmacol Sin 26:155–159

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Chu Y, Kordower JH (2007) Age-associated increases of alpha-synuclein in monkeys and humans are associated with nigrostriatal DA depletion: Is this the target for Parkinson’s disease? Neurobiol Dis 25:134–149

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordow-er JH (2009) Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 35:385–398

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Acknowledgments

This work was supported by grants from the National Foundation of Natural Science of China (No.81071018 and No.81371413), key project from Science and Technology Commission of Shanghai Municipality (13JC1401103), and project of Shanghai Municipal Commission of Health (XBR2013088). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Dr. Shun Yu from Xuanwu Hospital of the Capital University of Medical Sciences, Beijing, China, for kindly providing the human α-synuclein antibody for immunofluorescence.

Conflict of interest

The authors declare that they have no competing interests.

Authors’ contributions

WJ, Koprich JB, and Brotchie JM designed this study. HQ, WY, and YWB performed this study, analyzed data, and wrote the manuscript. XBG assisted in behavioral analysis. All authors discussed the results and provided comments on the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jonathan M. Brotchie or Jian Wang.

Additional information

Qing He and James B. Koprich contributed equally to this work.

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He, Q., Koprich, J.B., Wang, Y. et al. Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson’s Disease. Mol Neurobiol 53, 2258–2268 (2016). https://doi.org/10.1007/s12035-015-9173-7

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Keywords

  • Parkinson’s disease
  • α-Synuclein
  • Trehalose
  • DA
  • Autophagy