Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease.
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.
Ryu
Elizabeth J
EJ
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
HP
Angelastro
James M
JM
Vitolo
Ottavio V
OV
Ron
David
D
Greene
Lloyd A
LA
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D013565:Sympatholytics / Q000494:pharmacology*; D014158:Transcription, Genetic; D019892:eIF-2 Kinase / Q000235:genetics
D015655:1-Methyl-4-phenylpyridinium; D016627:Oxidopamine; D012333:RNA, Messenger; D012402:Rotenone; D013565:Sympatholytics; D019892:eIF-2 Kinase