CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism

Abstract

There is increasing evidence that neuron death in neurodegenerative diseases, such as Parkinson's disease, is due to the activation of programmed cell death. However, the upstream mediators of cell death remain largely unknown. One approach to the identification of upstream mediators is to perform gene expression analysis in disease models. Such analyses, performed in tissue culture models induced by neurotoxins, have identified up-regulation of CHOP/ GADD153, a transcription factor implicated in apoptosis due to endoplasmic reticulum stress or oxidative injury. To evaluate the disease-related significance of these findings, we have examined the expression of CHOP/GADD153 in neurotoxin models of parkinsonism in living animals. Nuclear expression of CHOP protein is observed in developmental and adult models of dopamine neuron death induced by intrastriatal injection of 6-hydroxydopamine (6OHDA) and in models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). CHOP is a mediator of neuron death in the adult 60HDA model because a null mutation results in a reduction in apoptosis. In the chronic MPTP model, however, while CHOP is robustly expressed, the null mutation does not protect from the loss of neurons. We conclude that the role of CHOP depends on the nature of the toxic stimulus. For 6OHDA, an oxidative metabolite of dopamine, it is a mediator of apoptotic death.

Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

“…However, target genes of the UPR ER were not significantly modulated. In agreement with this, CHOP upregulation was detected in animals treated with neurotoxins, but no evidence for UPR ER activation could be detected, 19 suggesting that also these druginduced animal models of parkinsonism might primarily be characterized by activation of the ISR alone. It is noted that oxidative stress has been shown earlier to lead to induction of the ISR and concomitant upregulation of CHOP expression without activation of the UPR ER in neuronal cells, 28 suggesting that deregulation of this pathway might be common in the development of neurodegenerative diseases.…”

“…14,15 Furthermore, CHOP is upregulated in neurotoxin models of parkinsonism in vivo. 19 We noted that genes induced in neuronal cells by both 6-OHDA (6-hydroxydopamine) and MPP þ (1-methyl-4-phenylpyridinium) were characteristic for activation of the ISR (gene set: neurotoxin treatment (ISR)), whereas only 6-OHDA would additionally activate genes characteristic for the UPR ER (e.g. Grp58, Xbp1) (gene set: neurotoxin treatment (UPR ER )).…”

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

“…The suppression of apoptosis in this model afforded by Myr-Akt was both substantial and lasting, as indicated by an almost complete preservation of the population of SN DA neurons at 28 days after toxin injection. In this respect, Myr-Akt differs from a number of other neuroprotective approaches that suppress cell death in the acute injury period but do not offer increases in DA neuron survival in the long term (28).…”

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

“…Recent studies investigating implication of ER stress in the pathophysiology of PD have reported increased UPR activity in the affected brain regions of PD patients and also in patients suffering from the related multi-systems atrophy syndrome [113,114]. It has been reported by Silva et al [115], that deficiency of CHOP, a key ER stress marker, protects the neonatal striatum from neurotoxicant 6-hydroxydopamine. Reports also showed that forced expression of ER stress sensor proteins, ATF6 alpha [117] and spliced XBP1 [116], confines neurotoxininduced dopaminergic neuronal death [117].…”