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PMID: 12486162 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 24 ·2002-12-15 ·Pages 10690-8

Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D, Greene LA

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 IRE1alpha 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.

MeSH Terms
1-Methyl-4-phenylpyridinium/pharmacology Animals Apoptosis Cells, Cultured Dose-Response Relationship, Drug Endoplasmic Reticulum/drug effects,physiology Ganglia, Sympathetic/drug effects,metabolism Gene Expression Profiling Gene Expression Regulation Mice Mice, Knockout Neurons/drug effects,metabolism Oxidopamine/pharmacology PC12 Cells Parkinson Disease/genetics,metabolism Protein Folding RNA, Messenger/biosynthesis Rats Rotenone/pharmacology Sympatholytics/pharmacology Transcription, Genetic eIF-2 Kinase/genetics
Chemicals
RNA, Messenger Sympatholytics Rotenone Oxidopamine PERK kinase eIF-2 Kinase 1-Methyl-4-phenylpyridinium
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Ryu Elizabeth J
Department of Pathology, Center for Neurobiology and Behavior, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Harding Heather P
Angelastro James M
Vitolo Ottavio V
Ron David
Greene Lloyd A
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2002-12-15
Pages
10690-8
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6758450
Subset
IM
Grants
NINDS NIH HHS · NS33689 · United States
NINDS NIH HHS · NS160636 · United States
NINDS NIH HHS · NS 436281 · United States
NIEHS NIH HHS · R01 ES008681 · United States
NINDS NIH HHS · P50 NS038370 · United States
NINDS NIH HHS · R01 NS033689 · United States
NIEHS NIH HHS · ES08681 · United States
NINDS NIH HHS · P50 NS38370 · United States
External Links
PubMed source PMC Full Text View journal details
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