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ER proteostasis disturbances in Parkinson's disease: novel insights.

Mercado G, Castillo V, Vidal R, Hetz C - Front Aging Neurosci (2015)

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile Santiago, Chile ; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile Santiago, Chile.

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In this article we discuss recent insights on the significance of ER stress as a driver of dopaminergic neuron loss in PD and the potential of targeting UPR components to augment the homeostatic capacity of the ER and reduce pro-apoptotic signals... The UPR is a signaling network mediated by the activation of three stress sensors located at the ER membrane, including inositol requiring kinase 1α (IRE1α), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK) (Figure 1A)... These UPR transducers control the expression of a variety of genes involved in almost every aspect of the secretory pathway, resulting in a reduction in the load of misfolded proteins at the ER... The mechanisms leading to ER stress in PD and the actual impact of the UPR on the degeneration cascade are just starting to be uncovered... We recently reported a set of in vivo studies uncovering the significance of the UPR transcription factor XBP1 in controlling the survival of dopaminergic neurons (Valdes et al., )... We found that the developmental ablation of Xbp1 in the nervous system preconditioned dopaminergic neurons and rendered them resistant to the PD-triggering neurotoxin 6-hydroxydopamine (6-OHDA) (Figure 1B)... This neuroprotective effect was accompanied by the up-regulation of several UPR effectors in the SNpc of animals in the absence of pro-apoptotic markers such as Chop... In agreement with this concept, establishment of an ER-hormesis condition (Matus et al., ) by the administration of low doses of the ER stress agent tunicamicyn on a rodent and fly model of PD selectively engaged adaptive UPR signaling events involving the expression of XBP1s (Fouillet et al., )... Using a gene therapy approach, we delivered active XBP1s into the SNpc of adult mice using adeno-asociated viral (AAVs) vectors (Valdes et al., )... This strategy conferred a dramatic protection against 6-OHDA (Figure 1C), in addition to reduce striatal denervation... The UPR is a double-edged sword, cytoprotective when activated to a moderate extent, but degenerative when it is sustained over time... Markers of PERK/eIF2α activation have been found in PD post-mortem brain tissue, where nigral dopaminergic neurons displaying αSynuclein inclusion are also positive for phosphorylated PERK and eIF2α (Hoozemans et al., )... Salubrinal, a small compound that enhances eIF2α (Boyce et al., ), was shown to delay disease onset and attenuate motor deficits induced by αSynuclein over-expression (Colla et al., )... Unexpectedly, although salubrinal treatment attenuated disease symptoms, its administration did not protect dopaminergic neurons from degeneration (Colla et al., )... In this context, the possible therapeutic potential and side effects of delivering active UPR components into the SNpc in the long term remains to be determined in non-human primates since most of the available studies only used rapid-evolving PD rodent models.

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Involvement of ER stress in PD. (A) Schematic representation of the three branches of the UPR. (B) Knockout (KO) animals for XBP1, CHOP or ATF6 have been tested to manipulate the UPR in PD models. (C) Images modified from Valdes et al. (2014): Wild-type mice were injected into the with (i) AAV expressing an shRNA against XBP1 (shXBP1/GFP), (ii) EGFP alone, or (iii) a vector to overexpress XBP1s. One month after injection, experimental PD was induced using the 6-OHDA model to monitor dopaminergic neuron loss at the SNpc. Green: AAV transduced cells expressing GFP. Red: dopaminergic neurons stained with anti-tyrosine hydroxylase (TH). Scale bar: 200 μm.
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Figure 1: Involvement of ER stress in PD. (A) Schematic representation of the three branches of the UPR. (B) Knockout (KO) animals for XBP1, CHOP or ATF6 have been tested to manipulate the UPR in PD models. (C) Images modified from Valdes et al. (2014): Wild-type mice were injected into the with (i) AAV expressing an shRNA against XBP1 (shXBP1/GFP), (ii) EGFP alone, or (iii) a vector to overexpress XBP1s. One month after injection, experimental PD was induced using the 6-OHDA model to monitor dopaminergic neuron loss at the SNpc. Green: AAV transduced cells expressing GFP. Red: dopaminergic neurons stained with anti-tyrosine hydroxylase (TH). Scale bar: 200 μm.

Mentions: The UPR is a signaling network mediated by the activation of three stress sensors located at the ER membrane, including inositol requiring kinase 1α (IRE1α), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK) (Figure 1A). These UPR transducers control the expression of a variety of genes involved in almost every aspect of the secretory pathway, resulting in a reduction in the load of misfolded proteins at the ER. Activation of the UPR improves the efficiency of protein folding and quality control mechanisms, in addition to enhance ER and Golgi biogenesis, protein secretion and the clearance of abnormally folded proteins through the autophagy and ER-associated degradation (ERAD) pathways. However, under chronic ER stress UPR sensors shifts their signaling toward induction of cell death by apoptosis (Urra et al., 2013).


ER proteostasis disturbances in Parkinson's disease: novel insights.

Mercado G, Castillo V, Vidal R, Hetz C - Front Aging Neurosci (2015)

Involvement of ER stress in PD. (A) Schematic representation of the three branches of the UPR. (B) Knockout (KO) animals for XBP1, CHOP or ATF6 have been tested to manipulate the UPR in PD models. (C) Images modified from Valdes et al. (2014): Wild-type mice were injected into the with (i) AAV expressing an shRNA against XBP1 (shXBP1/GFP), (ii) EGFP alone, or (iii) a vector to overexpress XBP1s. One month after injection, experimental PD was induced using the 6-OHDA model to monitor dopaminergic neuron loss at the SNpc. Green: AAV transduced cells expressing GFP. Red: dopaminergic neurons stained with anti-tyrosine hydroxylase (TH). Scale bar: 200 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4376001&req=5

Figure 1: Involvement of ER stress in PD. (A) Schematic representation of the three branches of the UPR. (B) Knockout (KO) animals for XBP1, CHOP or ATF6 have been tested to manipulate the UPR in PD models. (C) Images modified from Valdes et al. (2014): Wild-type mice were injected into the with (i) AAV expressing an shRNA against XBP1 (shXBP1/GFP), (ii) EGFP alone, or (iii) a vector to overexpress XBP1s. One month after injection, experimental PD was induced using the 6-OHDA model to monitor dopaminergic neuron loss at the SNpc. Green: AAV transduced cells expressing GFP. Red: dopaminergic neurons stained with anti-tyrosine hydroxylase (TH). Scale bar: 200 μm.
Mentions: The UPR is a signaling network mediated by the activation of three stress sensors located at the ER membrane, including inositol requiring kinase 1α (IRE1α), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK) (Figure 1A). These UPR transducers control the expression of a variety of genes involved in almost every aspect of the secretory pathway, resulting in a reduction in the load of misfolded proteins at the ER. Activation of the UPR improves the efficiency of protein folding and quality control mechanisms, in addition to enhance ER and Golgi biogenesis, protein secretion and the clearance of abnormally folded proteins through the autophagy and ER-associated degradation (ERAD) pathways. However, under chronic ER stress UPR sensors shifts their signaling toward induction of cell death by apoptosis (Urra et al., 2013).

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile Santiago, Chile ; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile Santiago, Chile.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In this article we discuss recent insights on the significance of ER stress as a driver of dopaminergic neuron loss in PD and the potential of targeting UPR components to augment the homeostatic capacity of the ER and reduce pro-apoptotic signals... The UPR is a signaling network mediated by the activation of three stress sensors located at the ER membrane, including inositol requiring kinase 1α (IRE1α), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK) (Figure 1A)... These UPR transducers control the expression of a variety of genes involved in almost every aspect of the secretory pathway, resulting in a reduction in the load of misfolded proteins at the ER... The mechanisms leading to ER stress in PD and the actual impact of the UPR on the degeneration cascade are just starting to be uncovered... We recently reported a set of in vivo studies uncovering the significance of the UPR transcription factor XBP1 in controlling the survival of dopaminergic neurons (Valdes et al., )... We found that the developmental ablation of Xbp1 in the nervous system preconditioned dopaminergic neurons and rendered them resistant to the PD-triggering neurotoxin 6-hydroxydopamine (6-OHDA) (Figure 1B)... This neuroprotective effect was accompanied by the up-regulation of several UPR effectors in the SNpc of animals in the absence of pro-apoptotic markers such as Chop... In agreement with this concept, establishment of an ER-hormesis condition (Matus et al., ) by the administration of low doses of the ER stress agent tunicamicyn on a rodent and fly model of PD selectively engaged adaptive UPR signaling events involving the expression of XBP1s (Fouillet et al., )... Using a gene therapy approach, we delivered active XBP1s into the SNpc of adult mice using adeno-asociated viral (AAVs) vectors (Valdes et al., )... This strategy conferred a dramatic protection against 6-OHDA (Figure 1C), in addition to reduce striatal denervation... The UPR is a double-edged sword, cytoprotective when activated to a moderate extent, but degenerative when it is sustained over time... Markers of PERK/eIF2α activation have been found in PD post-mortem brain tissue, where nigral dopaminergic neurons displaying αSynuclein inclusion are also positive for phosphorylated PERK and eIF2α (Hoozemans et al., )... Salubrinal, a small compound that enhances eIF2α (Boyce et al., ), was shown to delay disease onset and attenuate motor deficits induced by αSynuclein over-expression (Colla et al., )... Unexpectedly, although salubrinal treatment attenuated disease symptoms, its administration did not protect dopaminergic neurons from degeneration (Colla et al., )... In this context, the possible therapeutic potential and side effects of delivering active UPR components into the SNpc in the long term remains to be determined in non-human primates since most of the available studies only used rapid-evolving PD rodent models.

No MeSH data available.


Related in: MedlinePlus