Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease

Elizabeth J. Ryu, Heather P. Harding, James M Angelastro, Ottavio V. Vitolo, David Ron, Lloyd A. Greene

Research output: Contribution to journalArticle

428 Scopus citations

Abstract

6-Hydroxydopamine, 1-methyl-4-phenyl-pyridinium (MPP+), and rotenone cause the death of dopaminergic neurons in vitro and in vivo and are widely used to model Parkinson's disease. To identify regulated genes in such models, we performed serial analysis of gene expression on neuronal PC12 cells exposed to 6-hydroxydopamine. This revealed a striking increase in transcripts associated with the unfolded protein response. Immunoblotting confirmed phosphorylation of the key endoplasmic reticulum stress kinases IRE1 α and PERK (PKR-like ER kinase) and induction of their downstream targets. There was a similar response to MPP+ and rotenone, but not to other apoptotic initiators. As evidence that endoplasmic reticulum stress contributes to neuronal death, sympathetic neurons from PERK null mice in which the capacity to respond to endoplasmic reticulum stress is compromised were more sensitive to 6-hydroxydopamine. Our findings, coupled with evidence from familial forms of Parkinson's disease, raise the possibility of widespread involvement of endoplasmic reticulum stress and the unfolded protein response in the pathophysiology of this disease.

Original languageEnglish (US)
Pages (from-to)10690-10698
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number24
StatePublished - Dec 15 2002
Externally publishedYes

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Keywords

  • 6-hydroxydopamine
  • CHOP
  • Endoplasmic reticulum
  • Parkinson's disease
  • PERK
  • Unfolded protein response

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ryu, E. J., Harding, H. P., Angelastro, J. M., Vitolo, O. V., Ron, D., & Greene, L. A. (2002). Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease. Journal of Neuroscience, 22(24), 10690-10698.