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Coupling Endoplasmic Reticulum Stress to the Cell Death Program in Dopaminergic Cells: Effect of Paraquat

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Abstract

Parkinson’s disease (PD) features oxidative stress and accumulation of misfolded (unfolded, alternatively folded, or mutant) proteins with associated loss of dopaminergic neurons. Oxidative stress and the accumulated misfolded proteins elicit cellular responses that include an endoplasmic reticulum (ER) stress response that may protect cells against the toxic buildup of misfolded proteins. Chronic ER stress and accumulation of misfolded proteins in excessive amounts, however, overwhelm the cellular ‘quality control’ system and impair the protective mechanisms designed to promote correct folding and degrade faulty proteins, ultimately leading to organelle dysfunction and neuronal cell death. Paraquat belongs to a class of bipyridyl herbicides and triggers oxidative stress and dopaminergic cell death. Epidemiological studies suggest an increased risk for developing PD following chronic exposure to paraquat. The present study was carried out to determine the role of paraquat in triggering cellular stress particularly ER stress and to elucidate the pathways that couple ER stress to dopaminergic cell death. We demonstrate that paraquat triggers ER stress, cell dysfunction, and dopaminergic cell death. p23, a small co-chaperone protein, is cleaved during ER stress-induced cell death triggered by paraquat and blockage of the caspase cleavage site of p23 was associated with decreased cell death. Paraquat also inhibits proteasomal activity that may further trigger accumulation of misfolded proteins resulting in ER stress. Our results indicate a protective role for p23 in PD-related programmed cell death. The data also underscore the involvement of ER, caspases, and the proteasomal system in ER stress-induced cell death process.

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Abbreviations

ER:

Endoplasmic reticulum

Pcd:

Programmed cell death

eIF2α:

Eukaryotic initiation factor-2 alpha

GRP:

Glucose regulated protein

PD:

Parkinson’s disease (PD)

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Acknowledgments

We thank the members of the Bredesen laboratory and Andersen laboratory for helpful comments and discussions, and Molly Susag for administrative assistance. This work was supported by grants from the National Institutes of Health NS33376 to D.E.B. & R.V.R, and AG12282 to D.E.B.

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  1. The Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA, 94945, USA

    Shankar J. Chinta, Anand Rane, Karen S. Poksay, Dale E. Bredesen, Julie K. Andersen & Rammohan V. Rao

  2. University of California, San Francisco, San Francisco, CA, 94143, USA

    Dale E. Bredesen

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  1. Shankar J. Chinta
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  2. Anand Rane
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  3. Karen S. Poksay
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  6. Rammohan V. Rao
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Correspondence to Julie K. Andersen or Rammohan V. Rao.

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Chinta, S.J., Rane, A., Poksay, K.S. et al. Coupling Endoplasmic Reticulum Stress to the Cell Death Program in Dopaminergic Cells: Effect of Paraquat. Neuromol Med 10, 333–342 (2008). https://doi.org/10.1007/s12017-008-8047-9

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