Skip to main content

Advertisement

SpringerLink
Log in

PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α–Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson’s Disease

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Two recent studies demonstrated that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonists exerted neuroprotective effects in mouse model of Parkinson’s disease (PD). However, the underlying mechanisms remain unknown. Endoplasmic reticulum (ER) stress plays a major role in rotenone-induced dopaminergic neuronal degeneration. In the present study, we explored whether GW501516, a selective and high-affinity PPARβ/δ agonist, could protect the dopaminergic neurons against degeneration and improve PD behavior via suppressing the ER stress in the rotenone rat model of PD. GW501516 was administered intracerebroventricular infusion. Catalepsy and open field tests were used to test catalepsy and locomotor activities. The levels of dopamine and its metabolites were determined using high-performance liquid chromatography. Western blot and immunohistochemistry analysis were performed to assess dopaminergic neuronal degeneration. Quantitative real-time RT-PCR and Western blot analysis were executed to detect ER stress. TUNEL and immunohistochemistry assays were used to detect ER stress-mediated apoptosis. Our results showed that GW501516 ameliorated the catalepsy symptom and increased locomotor activity. Meanwhile, GW501516 partially reversed the loss of dopaminergic neurons. Moreover, GW501516 suppressed the activation of ER stress markers including inositol-requiring enzyme 1α (IRE1α) and caspase-12. Furthermore, GW501516 inhibited caspase-12-mediated neuronal apoptosis. These findings suggest that GW501516 conferred neuroprotection of not only biochemical and pathological attenuation but also behavioral improvement in the rotenone rat model of PD. More importantly, we demonstrated for the first time that suppressing IRE1α–caspase-12-mediated ER stress pathway may represent one potential mechanism underlying the neuroprotective effects of PPARβ/δ agonist in the rotenone rat model of PD.

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

Similar content being viewed by others

References

  1. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909

    Article  CAS  PubMed  Google Scholar 

  2. Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D, Greene LA (2002) Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J Neurosci: Off J Soc Neurosci 22(24):10690–10698

    CAS  Google Scholar 

  3. Wang HQ, Takahashi R (2007) Expanding insights on the involvement of endoplasmic reticulum stress in Parkinson’s disease. Antioxid Redox Signal 9(5):553–561. doi:10.1089/ars.2006.1524

    Article  CAS  PubMed  Google Scholar 

  4. Roussel BD, Kruppa AJ, Miranda E, Crowther DC, Lomas DA, Marciniak SJ (2013) Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol 12(1):105–118. doi:10.1016/S1474-4422(12)70238-7

    Article  CAS  PubMed  Google Scholar 

  5. Kadowaki H, Nishitoh H, Ichijo H (2004) Survival and apoptosis signals in ER stress: the role of protein kinases. J Chem Neuroanat 28(1-2):93–100. doi:10.1016/j.jchemneu.2004.05.004

    Article  CAS  PubMed  Google Scholar 

  6. Marciniak SJ, Ron D (2006) Endoplasmic reticulum stress signaling in disease. Physiol Rev 86(4):1133–1149. doi:10.1152/physrev.00015.2006

    Article  CAS  PubMed  Google Scholar 

  7. Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115(10):2656–2664. doi:10.1172/JCI26373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2(6):326–332. doi:10.1038/35014014

    Article  CAS  PubMed  Google Scholar 

  9. Pfaffenbach KT, Lee AS (2011) The critical role of GRP78 in physiologic and pathologic stress. Curr Opin Cell Biol 23(2):150–156. doi:10.1016/j.ceb.2010.09.007

    Article  CAS  PubMed  Google Scholar 

  10. Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7(9):880–885. doi:10.1038/sj.embor.7400779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13(2):89–102. doi:10.1038/nrm3270

    CAS  PubMed  Google Scholar 

  12. Chen YY, Chen G, Fan Z, Luo J, Ke ZJ (2008) GSK3beta and endoplasmic reticulum stress mediate rotenone-induced death of SK-N-MC neuroblastoma cells. Biochem Pharmacol 76(1):128–138. doi:10.1016/j.bcp.2008.04.010

    Article  CAS  PubMed  Google Scholar 

  13. Wu L, Tian YY, Shi JP, Xie W, Shi JQ, Lu J, Zhang YD (2013) Inhibition of endoplasmic reticulum stress is involved in the neuroprotective effects of candesartan cilexitil in the rotenone rat model of Parkinson’s disease. Neurosci Lett 548:50–55. doi:10.1016/j.neulet.2013.06.008

    Article  CAS  PubMed  Google Scholar 

  14. Goswami P, Gupta S, Biswas J, Joshi N, Swarnkar S, Nath C, Singh S (2014) Endoplasmic reticulum stress plays a key role in rotenone-induced apoptotic death of neurons. Mol Neurobiol. doi:10.1007/s12035-014-9001-5

    PubMed  Google Scholar 

  15. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta.pdf. Nature 403(6765):98–103

    Article  CAS  PubMed  Google Scholar 

  16. Nakagawa T, Yuan J (2000) Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 150(4):887–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T et al (2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev 58(4):726–741. doi:10.1124/pr.58.4.5

    Article  CAS  PubMed  Google Scholar 

  18. Moreno S, Farioli-Vecchioli S, Ceru MP (2004) Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience 123(1):131–145

    Article  CAS  PubMed  Google Scholar 

  19. Woods JW, Tanen M, Figueroa DJ, Biswas C, Zycband E, Moller DE, Austin CP, Berger JP (2003) Localization of PPARdelta in murine central nervous system: expression in oligodendrocytes and neurons. Brain Res 975(1-2):10–21

    Article  CAS  PubMed  Google Scholar 

  20. Iwashita A, Muramatsu Y, Yamazaki T, Muramoto M, Kita Y, Yamazaki S, Mihara K, Moriguchi A et al (2007) Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo. J Pharmacol Exp Ther 320(3):1087–1096. doi:10.1124/jpet.106.115758

    Article  CAS  PubMed  Google Scholar 

  21. Martin HL, Mounsey RB, Sathe K, Mustafa S, Nelson MC, Evans RM, Teismann P (2013) A peroxisome proliferator-activated receptor-delta agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Neuroscience 240:191–203. doi:10.1016/j.neuroscience.2013.02.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Palomer X, Capdevila-Busquets E, Botteri G, Salvado L, Barroso E, Davidson MM, Michalik L, Wahli W et al (2014) PPARbeta/delta attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells. Int J Cardiol 174(1):110–118. doi:10.1016/j.ijcard.2014.03.176

    Article  PubMed  Google Scholar 

  23. Salvado L, Barroso E, Gomez-Foix AM, Palomer X, Michalik L, Wahli W, Vazquez-Carrera M (2014) PPARbeta/delta prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia 57(10):2126–2135. doi:10.1007/s00125-014-3331-8

    Article  CAS  PubMed  Google Scholar 

  24. Alam M, Schmidt WJ (2002) Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res 136(1):317–324

    Article  CAS  PubMed  Google Scholar 

  25. Alam M, Schmidt WJ (2004) L-DOPA reverses the hypokinetic behaviour and rigidity in rotenone-treated rats. Behav Brain Res 153(2):439–446. doi:10.1016/j.bbr.2003.12.021

    Article  CAS  PubMed  Google Scholar 

  26. Zhu D, Tong Q, Liu W, Tian M, Xie W, Ji L, Shi J (2014) Angiotensin (1-7) protects against stress-induced gastric lesions in rats. Biochem Pharmacol 87(3):467–476. doi:10.1016/j.bcp.2013.10.026

    Article  CAS  PubMed  Google Scholar 

  27. Quinn LP, Crook B, Hows ME, Vidgeon-Hart M, Chapman H, Upton N, Medhurst AD, Virley DJ (2008) The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson’s disease through inhibition of monoamine oxidase B. Br J Pharmacol 154(1):226–233. doi:10.1038/bjp.2008.78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Iwashita A, Yamazaki S, Mihara K, Hattori K, Yamamoto H, Ishida J, Matsuoka N, Mutoh S (2004) Neuroprotective effects of a novel poly(ADP-ribose) polymerase-1 inhibitor, 2-[3-[4-(4-chlorophenyl)-1-piperazinyl] propyl]-4(3H)-quinazolinone (FR255595), in an in vitro model of cell death and in mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Pharmacol Exp Ther 309(3):1067–1078. doi:10.1124/jpet.103.064642

    Article  CAS  PubMed  Google Scholar 

  29. Ferreiro E, Resende R, Costa R, Oliveira CR, Pereira CM (2006) An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol Dis 23(3):669–678. doi:10.1016/j.nbd.2006.05.011

    Article  CAS  PubMed  Google Scholar 

  30. Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276(17):13935–13940. doi:10.1074/jbc.M010677200

    Article  CAS  PubMed  Google Scholar 

  31. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287(5453):664–666

    Article  CAS  PubMed  Google Scholar 

  32. Upton JP, Wang L, Han D, Wang ES, Huskey NE, Lim L, Truitt M, McManus MT et al (2012) IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 338(6108):818–822. doi:10.1126/science.1226191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen Y, Brandizzi F (2013) IRE1: ER stress sensor and cell fate executor. Trends Cell Biol 23(11):547–555. doi:10.1016/j.tcb.2013.06.005

    Article  CAS  PubMed  Google Scholar 

  34. Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA et al (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138(3):562–575. doi:10.1016/j.cell.2009.07.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chaudhari N, Talwar P, Parimisetty A, Lefebvre d’Hellencourt C, Ravanan P (2014) A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci 8:213. doi:10.3389/fncel.2014.00213

    Article  PubMed  PubMed Central  Google Scholar 

  36. Barroso E, Eyre E, Palomer X, Vazquez-Carrera M (2011) The peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) agonist GW501516 prevents TNF-alpha-induced NF-kappaB activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1. Biochem Pharmacol 81(4):534–543. doi:10.1016/j.bcp.2010.12.004

    Article  CAS  PubMed  Google Scholar 

  37. Su X, Zhou G, Wang Y, Yang X, Li L, Yu R, Li D (2014) The PPARbeta/delta agonist GW501516 attenuates peritonitis in peritoneal fibrosis via inhibition of TAK1-NFkappaB pathway in rats. Inflammation 37(3):729–737. doi:10.1007/s10753-013-9791-z

    Article  CAS  PubMed  Google Scholar 

  38. Zhu B, Ferry CH, Markell LK, Blazanin N, Glick AB, Gonzalez FJ, Peters JM (2014) The nuclear receptor peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress. J Biol Chem 289(29):20102–20119. doi:10.1074/jbc.M114.551069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Natural Science of China (No. 81271418) and Natural Science Foundation of Jiangsu Province (No. BK201254).

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Geriatrics, Huai’an First People’s Hospital, Nanjing Medical University, P.O. Box 223300, No. 6 Beijing Road West, Huai’an, People’s Republic of China

    Qiang Tong

  2. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, People’s Republic of China

    Liang Wu, Qing Gao, Zhou Ou & Yingdong Zhang

  3. Department of Pharmacology, School of Pharmacy, Nanjing Medical University, P.O. Box 211166, No. 818 Tianyuan East Road, Jiangning District, Nanjing, People’s Republic of China

    Dongya Zhu

Authors
  1. Qiang Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhou Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dongya Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yingdong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yingdong Zhang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tong, Q., Wu, L., Gao, Q. et al. PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α–Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson’s Disease. Mol Neurobiol 53, 3822–3831 (2016). https://doi.org/10.1007/s12035-015-9309-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9309-9

Keywords

Search

Navigation