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The unfolded protein response in neurodegenerative diseases: a neuropathological perspective.

Scheper W, Hoozemans JJ - Acta Neuropathol. (2015)

Bottom Line: More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR.Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results.The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.

ABSTRACT
The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prion disease. Over the last decade, the UPR has been addressed in an increasing number of studies on neurodegeneration. The involvement of the UPR has been investigated in human neuropathology across different neurological diseases, as well as in cell and mouse models for neurodegeneration. Studies using different disease models display discrepancies on the role and function of the UPR during neurodegeneration, which can often be attributed to differences in methodology. In this review, we will address the importance of investigation of human brain material for the interpretation of the role of the UPR in neurological diseases. We will discuss evidence for UPR activation in neurodegenerative diseases, and the methodology to study UPR activation and its connection to brain pathology will be addressed. More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR. Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results. The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.

No MeSH data available.


Related in: MedlinePlus

The unfolded protein response. The unfolded protein response consists of three independent signaling pathways that work in parallel and are activated upon accumulation of unfolded proteins inside the ER. Each signaling pathway is defined by the different ER-resident transmembrane proteins that act as ER stress sensors: RNA-activated protein kinase R (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol requiring enzyme 1 (IRE1). Activation of the UPR leads to an overall translational block and specific activation of ER stress responsive genes, which will increase the protein folding capacity and decrease the protein folding load in the ER. See text for further details
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Fig1: The unfolded protein response. The unfolded protein response consists of three independent signaling pathways that work in parallel and are activated upon accumulation of unfolded proteins inside the ER. Each signaling pathway is defined by the different ER-resident transmembrane proteins that act as ER stress sensors: RNA-activated protein kinase R (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol requiring enzyme 1 (IRE1). Activation of the UPR leads to an overall translational block and specific activation of ER stress responsive genes, which will increase the protein folding capacity and decrease the protein folding load in the ER. See text for further details

Mentions: The IRE1, PERK and ATF6 pathways together comprise an intricate network that has a broad range of transcriptional and translational targets. The UPR is closely connected to the proteolytic machinery of the cell. Proteins that misfold in the ER are exported to the cytosol and degraded by the proteasome [80]. However, once the UPR is activated, autophagy is increased and this becomes the major proteolytic system [5, 24, 69, 73, 90]. Although many mechanistic details and additional regulatory pathways are still being uncovered, the core signaling of the mammalian UPR had been unraveled by 2002 (Fig. 1).Fig. 1


The unfolded protein response in neurodegenerative diseases: a neuropathological perspective.

Scheper W, Hoozemans JJ - Acta Neuropathol. (2015)

The unfolded protein response. The unfolded protein response consists of three independent signaling pathways that work in parallel and are activated upon accumulation of unfolded proteins inside the ER. Each signaling pathway is defined by the different ER-resident transmembrane proteins that act as ER stress sensors: RNA-activated protein kinase R (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol requiring enzyme 1 (IRE1). Activation of the UPR leads to an overall translational block and specific activation of ER stress responsive genes, which will increase the protein folding capacity and decrease the protein folding load in the ER. See text for further details
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4541706&req=5

Fig1: The unfolded protein response. The unfolded protein response consists of three independent signaling pathways that work in parallel and are activated upon accumulation of unfolded proteins inside the ER. Each signaling pathway is defined by the different ER-resident transmembrane proteins that act as ER stress sensors: RNA-activated protein kinase R (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol requiring enzyme 1 (IRE1). Activation of the UPR leads to an overall translational block and specific activation of ER stress responsive genes, which will increase the protein folding capacity and decrease the protein folding load in the ER. See text for further details
Mentions: The IRE1, PERK and ATF6 pathways together comprise an intricate network that has a broad range of transcriptional and translational targets. The UPR is closely connected to the proteolytic machinery of the cell. Proteins that misfold in the ER are exported to the cytosol and degraded by the proteasome [80]. However, once the UPR is activated, autophagy is increased and this becomes the major proteolytic system [5, 24, 69, 73, 90]. Although many mechanistic details and additional regulatory pathways are still being uncovered, the core signaling of the mammalian UPR had been unraveled by 2002 (Fig. 1).Fig. 1

Bottom Line: More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR.Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results.The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.

ABSTRACT
The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prion disease. Over the last decade, the UPR has been addressed in an increasing number of studies on neurodegeneration. The involvement of the UPR has been investigated in human neuropathology across different neurological diseases, as well as in cell and mouse models for neurodegeneration. Studies using different disease models display discrepancies on the role and function of the UPR during neurodegeneration, which can often be attributed to differences in methodology. In this review, we will address the importance of investigation of human brain material for the interpretation of the role of the UPR in neurological diseases. We will discuss evidence for UPR activation in neurodegenerative diseases, and the methodology to study UPR activation and its connection to brain pathology will be addressed. More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR. Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results. The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.

No MeSH data available.


Related in: MedlinePlus