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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

UPR activation in Alzheimer’s disease. Immunohistochemical detection and antibodies used for the detection of UPR markers and phosphorylated tau (AT8, AT100 and AT270) have been described previously [41, 42]. Shown are pictures of the hippocampal sub-area subiculum of a control case (CTRL, Braak 0) and an AD case (Braak 5). a–c pPERK is detected by immunohistochemistry in pyramidal neurons of an AD case and is absent in a control case showing no AD pathology. pPERK is present in granules which can be defined as granulovacuolar degeneration. d–f p-eIF2α immunohistochemistry on the same area shown for the control and AD case in a–c. Also p-eIF2α can be detected as granules in pyramidal neurons. g–i pIRE1α is also detected in pyramidal neurons in the subiculum of an AD case and is absent in a control case (shown is the same area as indicated in a–c). Similar granular structures are detected as observed with pPERK and p-eIF2α immunohistochemistry. j–k UPR markers in AD are localized in neurons showing increased presence of phosphorylated Tau protein; j Double immunolabeling for pPERK (brown) and AT8 (red, pTau Ser202), k pPERK (brown) and AT100 (red, pTau Ser212 and Thr 214) and l pPERK (brown) and AT270 (red, pTau Thr181). Sections were counterstained with haematoxylin (blue). Scale bara, b, d, e, g, h 300 μm; c, f, i–l 40 μm
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Fig2: UPR activation in Alzheimer’s disease. Immunohistochemical detection and antibodies used for the detection of UPR markers and phosphorylated tau (AT8, AT100 and AT270) have been described previously [41, 42]. Shown are pictures of the hippocampal sub-area subiculum of a control case (CTRL, Braak 0) and an AD case (Braak 5). a–c pPERK is detected by immunohistochemistry in pyramidal neurons of an AD case and is absent in a control case showing no AD pathology. pPERK is present in granules which can be defined as granulovacuolar degeneration. d–f p-eIF2α immunohistochemistry on the same area shown for the control and AD case in a–c. Also p-eIF2α can be detected as granules in pyramidal neurons. g–i pIRE1α is also detected in pyramidal neurons in the subiculum of an AD case and is absent in a control case (shown is the same area as indicated in a–c). Similar granular structures are detected as observed with pPERK and p-eIF2α immunohistochemistry. j–k UPR markers in AD are localized in neurons showing increased presence of phosphorylated Tau protein; j Double immunolabeling for pPERK (brown) and AT8 (red, pTau Ser202), k pPERK (brown) and AT100 (red, pTau Ser212 and Thr 214) and l pPERK (brown) and AT270 (red, pTau Thr181). Sections were counterstained with haematoxylin (blue). Scale bara, b, d, e, g, h 300 μm; c, f, i–l 40 μm

Mentions: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and the most common form of dementia. Deposits of aggregated proteins are a prominent neuropathological hallmark of AD: intracellular aggregates of tau in the neurofibrillary tangles (NFTs), dystrophic neurites and neuropil threads, and extracellular aggregates of β-amyloid (Aβ) in the senile plaques. AD thus represents a prime example of a protein folding disease [106]. Markers specific for UPR activation are increased in AD brain tissue compared to non-demented control brain tissue (Fig. 2). GRP78 is increased in AD in the hippocampus and temporal cortex and various studies from different groups have shown increased presence of phosphorylated (p)PERK, pIRE1, and p-eIF2α in AD neurons [15, 29, 41, 42, 103, 111]. These markers appear either in morphologically healthy neurons or in neurons with abnormally phosphorylated tau protein, but are almost absent from NFT-containing neurons. Overall, the levels of GRP78 and the occurrence of pPERK in AD neurons correlate very well with the presence of abnormally phosphorylated tau and the Braak staging for NFTs [41]. These observations indicate that the UPR is involved in the early stages of AD pathology.Fig. 2


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

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

UPR activation in Alzheimer’s disease. Immunohistochemical detection and antibodies used for the detection of UPR markers and phosphorylated tau (AT8, AT100 and AT270) have been described previously [41, 42]. Shown are pictures of the hippocampal sub-area subiculum of a control case (CTRL, Braak 0) and an AD case (Braak 5). a–c pPERK is detected by immunohistochemistry in pyramidal neurons of an AD case and is absent in a control case showing no AD pathology. pPERK is present in granules which can be defined as granulovacuolar degeneration. d–f p-eIF2α immunohistochemistry on the same area shown for the control and AD case in a–c. Also p-eIF2α can be detected as granules in pyramidal neurons. g–i pIRE1α is also detected in pyramidal neurons in the subiculum of an AD case and is absent in a control case (shown is the same area as indicated in a–c). Similar granular structures are detected as observed with pPERK and p-eIF2α immunohistochemistry. j–k UPR markers in AD are localized in neurons showing increased presence of phosphorylated Tau protein; j Double immunolabeling for pPERK (brown) and AT8 (red, pTau Ser202), k pPERK (brown) and AT100 (red, pTau Ser212 and Thr 214) and l pPERK (brown) and AT270 (red, pTau Thr181). Sections were counterstained with haematoxylin (blue). Scale bara, b, d, e, g, h 300 μm; c, f, i–l 40 μm
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Fig2: UPR activation in Alzheimer’s disease. Immunohistochemical detection and antibodies used for the detection of UPR markers and phosphorylated tau (AT8, AT100 and AT270) have been described previously [41, 42]. Shown are pictures of the hippocampal sub-area subiculum of a control case (CTRL, Braak 0) and an AD case (Braak 5). a–c pPERK is detected by immunohistochemistry in pyramidal neurons of an AD case and is absent in a control case showing no AD pathology. pPERK is present in granules which can be defined as granulovacuolar degeneration. d–f p-eIF2α immunohistochemistry on the same area shown for the control and AD case in a–c. Also p-eIF2α can be detected as granules in pyramidal neurons. g–i pIRE1α is also detected in pyramidal neurons in the subiculum of an AD case and is absent in a control case (shown is the same area as indicated in a–c). Similar granular structures are detected as observed with pPERK and p-eIF2α immunohistochemistry. j–k UPR markers in AD are localized in neurons showing increased presence of phosphorylated Tau protein; j Double immunolabeling for pPERK (brown) and AT8 (red, pTau Ser202), k pPERK (brown) and AT100 (red, pTau Ser212 and Thr 214) and l pPERK (brown) and AT270 (red, pTau Thr181). Sections were counterstained with haematoxylin (blue). Scale bara, b, d, e, g, h 300 μm; c, f, i–l 40 μm
Mentions: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and the most common form of dementia. Deposits of aggregated proteins are a prominent neuropathological hallmark of AD: intracellular aggregates of tau in the neurofibrillary tangles (NFTs), dystrophic neurites and neuropil threads, and extracellular aggregates of β-amyloid (Aβ) in the senile plaques. AD thus represents a prime example of a protein folding disease [106]. Markers specific for UPR activation are increased in AD brain tissue compared to non-demented control brain tissue (Fig. 2). GRP78 is increased in AD in the hippocampus and temporal cortex and various studies from different groups have shown increased presence of phosphorylated (p)PERK, pIRE1, and p-eIF2α in AD neurons [15, 29, 41, 42, 103, 111]. These markers appear either in morphologically healthy neurons or in neurons with abnormally phosphorylated tau protein, but are almost absent from NFT-containing neurons. Overall, the levels of GRP78 and the occurrence of pPERK in AD neurons correlate very well with the presence of abnormally phosphorylated tau and the Braak staging for NFTs [41]. These observations indicate that the UPR is involved in the early stages of AD pathology.Fig. 2

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