Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cellular Models of Parkinson's Disease

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.

ER stress and neurodegenerative diseases

“…36,37 These changes were specific for the two PD mimetic and rotenone, a mitochondrial inhibitor that causes degeneration of dopaminergic neurons but not with other agents. 37 There were some differences in the magnitude and pattern of gene responses induced by 6-OHDA and MPP þ , but both compounds clearly elicited an UPR in the neurons. 36 Experiments carried out using neuronal cultures from Perk gene deleted mice revealed an increased sensitivity of the cells against treatment with 6-OHDA.…”

“…36,37 Compounds, such as 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1, 2,3,6-tetrahydroyridine or its active derivative, MPP þ , induce oxidative stress and impair mitochondrial respiration and energy metabolism. Recent studies with cultured neuronal cells, including dopaminergic neurons, showed that these compounds trigger ER stress and induce a number of genes.…”

“…Recent studies with cultured neuronal cells, including dopaminergic neurons, showed that these compounds trigger ER stress and induce a number of genes. 36,37 Gene profiling revealed that both ER chaperones and other components of the UPR such as the transcription factor, CHOP/Gadd153 were upregulated in exposed cells, in addition to the phosphorylation of the ER stress kinases, IRE and PERK. 36,37 These changes were specific for the two PD mimetic and rotenone, a mitochondrial inhibitor that causes degeneration of dopaminergic neurons but not with other agents.…”

“…36,37 Gene profiling revealed that both ER chaperones and other components of the UPR such as the transcription factor, CHOP/Gadd153 were upregulated in exposed cells, in addition to the phosphorylation of the ER stress kinases, IRE and PERK. 36,37 These changes were specific for the two PD mimetic and rotenone, a mitochondrial inhibitor that causes degeneration of dopaminergic neurons but not with other agents. 37 There were some differences in the magnitude and pattern of gene responses induced by 6-OHDA and MPP þ , but both compounds clearly elicited an UPR in the neurons.…”

Roles of CHOP/GADD153 in endoplasmic reticulum stress

“…100,101 Since NO plays an important role in dopaminergic neurodegeneration induced by another dopaminergic neurodegeneration neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), it is worth determining if disruption of the CHOP gene prevents neuronal cells from MPTP-induced apoptosis. 102 Several lines of evidence suggested a link between dysfunction of the ERAD system and the pathogenesis of Parkinson's and polyglutamine disease. Mutation of parkin, that is an E3 ubiquitin ligase, is one of the major causes of familial Parkinson's disease.…”