Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells - PubMed (original) (raw)

Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells

H J Rideout et al. J Neurochem. 2001 Aug.

Free article

Abstract

Proteasomal dysfunction has been recently implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and diffuse Lewy body disease. We have developed an in vitro model of proteasomal dysfunction by applying pharmacological inhibitors of the proteasome, lactacystin or ZIE[O-tBu]-A-leucinal (PSI), to dopaminergic PC12 cells. Proteasomal inhibition caused a dose-dependent increase in death of both naive and neuronally differentiated PC12 cells, which could be prevented by caspase inhibition or CPT-cAMP. A percentage of the surviving cells contained discrete cytoplasmic ubiquitinated inclusions, some of which also contained synuclein-1, the rat homologue of human alpha-synuclein. However the total level of synuclein-1 was not altered by proteasomal inhibition. The ubiquitinated inclusions were present only within surviving cells, and their number was increased if cell death was prevented. We have thus replicated, in this model system, the two cardinal pathological features of Lewy body diseases, neuronal death and the formation of cytoplasmic ubiquitinated inclusions. Our findings suggest that inclusion body formation and cell death may be dissociated from one another.

PubMed Disclaimer

Similar articles

• Proteasomal inhibition-induced inclusion formation and death in cortical neurons require transcription and ubiquitination.
  Rideout HJ, Stefanis L. Rideout HJ, et al. Mol Cell Neurosci. 2002 Oct;21(2):223-38. doi: 10.1006/mcne.2002.1173. Mol Cell Neurosci. 2002. PMID: 12401444
• Synphilin-1 degradation by the ubiquitin-proteasome pathway and effects on cell survival.
  Lee G, Junn E, Tanaka M, Kim YM, Mouradian MM. Lee G, et al. J Neurochem. 2002 Oct;83(2):346-52. doi: 10.1046/j.1471-4159.2002.01136.x. J Neurochem. 2002. PMID: 12423244
• Alpha-synuclein-enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons.
  McLean PJ, Kawamata H, Hyman BT. McLean PJ, et al. Neuroscience. 2001;104(3):901-12. doi: 10.1016/s0306-4522(01)00113-0. Neuroscience. 2001. PMID: 11440819
• Alpha synuclein in neurodegenerative disorders: murderer or accomplice?
  Mezey E, Dehejia A, Harta G, Papp MI, Polymeropoulos MH, Brownstein MJ. Mezey E, et al. Nat Med. 1998 Jul;4(7):755-7. doi: 10.1038/nm0798-755. Nat Med. 1998. PMID: 9662355 Review. No abstract available.
• Ubiquitinated inclusions and neuronal cell death.
  Lang-Rollin I, Rideout H, Stefanis L. Lang-Rollin I, et al. Histol Histopathol. 2003 Apr;18(2):509-17. doi: 10.14670/HH-18.509. Histol Histopathol. 2003. PMID: 12647802 Review.

Cited by

• Protein degradation pathways in Parkinson's disease: curse or blessing.
  Ebrahimi-Fakhari D, Wahlster L, McLean PJ. Ebrahimi-Fakhari D, et al. Acta Neuropathol. 2012 Aug;124(2):153-72. doi: 10.1007/s00401-012-1004-6. Epub 2012 Jun 29. Acta Neuropathol. 2012. PMID: 22744791 Free PMC article. Review.
• The neurotoxin, MPP+, induces hyperphosphorylation of Tau, in the presence of alpha-Synuclein, in SH-SY5Y neuroblastoma cells.
  Duka T, Sidhu A. Duka T, et al. Neurotox Res. 2006 Aug;10(1):1-10. doi: 10.1007/BF03033329. Neurotox Res. 2006. PMID: 17000465
• Heat shock protein defenses in the neocortex and allocortex of the telencephalon.
  Posimo JM, Weilnau JN, Gleixner AM, Broeren MT, Weiland NL, Brodsky JL, Wipf P, Leak RK. Posimo JM, et al. Neurobiol Aging. 2015 May;36(5):1924-37. doi: 10.1016/j.neurobiolaging.2015.02.011. Epub 2015 Feb 18. Neurobiol Aging. 2015. PMID: 25771395 Free PMC article.
• Is Parkinson's disease a prion disorder?
  Olanow CW, Prusiner SB. Olanow CW, et al. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12571-2. doi: 10.1073/pnas.0906759106. Epub 2009 Jul 28. Proc Natl Acad Sci U S A. 2009. PMID: 19666621 Free PMC article. No abstract available.
• Cyclin-dependent kinase activity is required for apoptotic death but not inclusion formation in cortical neurons after proteasomal inhibition.
  Rideout HJ, Wang Q, Park DS, Stefanis L. Rideout HJ, et al. J Neurosci. 2003 Feb 15;23(4):1237-45. doi: 10.1523/JNEUROSCI.23-04-01237.2003. J Neurosci. 2003. PMID: 12598612 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Ovid Technologies, Inc.
  • Wiley