Ovine PrP transgenic Drosophila show reduced locomotor activity and decreased survival

2012 ◽  
Vol 444 (3) ◽  
pp. 487-495 ◽  
Author(s):  
Alana M. Thackray ◽  
Farooq Muhammad ◽  
Chang Zhang ◽  
Ying Di ◽  
Thomas R. Jahn ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Prion Protein ◽  
Germ Line ◽  
Critical Role ◽  
Neuronal Cell ◽  
Single Amino Acid ◽  
Site Specific ◽  
Protein Levels ◽  
Neuronal Cell Bodies ◽  
Transgenic Drosophila

Drosophila have emerged as a model system to study mammalian neurodegenerative diseases. In the present study we have generated Drosophila transgenic for ovine PrP (prion protein) to begin to establish an invertebrate model of ovine prion disease. We generated Drosophila transgenic for polymorphic variants of ovine PrP by PhiC31 site-specific germ-line transformation under expression control by the bi-partite GAL4/UAS (upstream activating sequence) system. Site-specific transgene insertion in the fly genome allowed us to test the hypothesis that single amino acid codon changes in ovine PrP modulate prion protein levels and the phenotype of the fly when expressed in the Drosophila nervous system. The Arg154 ovine PrP variants showed higher levels of PrP expression in neuronal cell bodies and insoluble PrP conformer than did His154 variants. High levels of ovine PrP expression in Drosophila were associated with phenotypic effects, including reduced locomotor activity and decreased survival. Significantly, the present study highlights a critical role for helix-1 in the formation of distinct conformers of ovine PrP, since expression of His154 variants were associated with decreased survival in the absence of high levels of PrP accumulation. Collectively, the present study shows that variants of the ovine PrP are associated with different spontaneous detrimental effects in ovine PrP transgenic Drosophila.

scholarly journals A Critical Role for Macrophages Near Axotomized Neuronal Cell Bodies in Stimulating Nerve Regeneration

2013 ◽  
Vol 33 (41) ◽  
pp. 16236-16248 ◽  
Author(s):  
J. P. Niemi ◽  
A. DeFrancesco-Lisowitz ◽  
L. Roldan-Hernandez ◽  
J. A. Lindborg ◽  
D. Mandell ◽  
...  
Keyword(s):  
Nerve Regeneration ◽  
Critical Role ◽  
Neuronal Cell ◽  
Neuronal Cell Bodies

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2021 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Young Min Oh ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2020 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2020 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

scholarly journals Prion peptide-mediated calcium level alteration governs neuronal cell damage through AMPK-autophagy flux

2020 ◽  
Author(s):  
Ji-Hong Moon ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Intracellular Calcium ◽  
Prion Protein ◽  
Prion Diseases ◽  
Critical Role ◽  
Neuronal Cell ◽  
Autophagic Cell Death ◽  
Autophagy Flux ◽  
Human Prion Protein ◽  
Ampk Activity

Abstract Background The distinctive molecular structure of the prion protein, PrPsc, is established only in mammals with infectious prion diseases. Prion protein characterizes either the transmissible pathogen itself or a primary constituent of the disease. Our report suggested that prion-mediated neuronal cell death is triggered by the autophagy flux. However, the alteration of intracellular calcium levels, AMPK activity in prion models has not been described. This study is focused on the effect of the changes in intracellular calcium levels on AMPK/autophagy flux pathway and PrP (106–126)-induced neurotoxicity. Methods Western blot and Immunocytochemistry was used to detect AMPK and autophagy-related protein expression. Flow cytometry and a TdT-mediated biotin-16-dUTP nick-end labeling (TUNEL) assay were used to detect the percentage of apoptotic cells. Calcium measurement was employed using fluo-4 by confocal microscope. Results We examined the effect of calcium homeostasis alterations induced by human prion protein on the autophagy flux in neuronal cells. Treatment with human prion protein increased the intracellular calcium concentration and induced cell death in primary neurons as well as in a neuronal cell line. Using pharmacological inhibitors, we showed that the L-type calcium channel is involved in the cellular entry of calcium ions. Inhibition of calcium uptake prevented autophagic cell death and reduction in AMP-activated protein kinase (AMPK) activity induced by human prion protein. Conclusion Our data demonstrated that prion protein-mediated calcium inflow plays a pivotal role in prion protein-induced autophagic cell death, and reduction in AMPK activity in neurons. Altogether, our results suggest that calcium influx might play a critical role in neurodegenerative diseases, including prion diseases.

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2020 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In this study, we investigated the effects of baicalein on the development of prion diseases. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2020 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

scholarly journals Immunohistochemical Detection of Prion Protein in Sheep with Scrapie

1993 ◽  
Vol 5 (3) ◽  
pp. 309-316 ◽  
Author(s):  
Janice M. Miller ◽  
Allen L. Jenny ◽  
William D. Taylor ◽  
Richard F. Marsh ◽  
Richard Rubenstein ◽  
...  
Keyword(s):  
Prion Protein ◽  
Neuronal Cell ◽  
Normal Brain ◽  
Tissue Samples ◽  
Tissue Sections ◽  
Clinically Normal ◽  
Neuronal Cell Bodies ◽  
Histopathologic Evaluation ◽  
Transmissible Mink Encephalopathy ◽  
The Brain

Prion protein (PrP), which is involved in the pathogenesis of scrapie, occurs in 2 forms. The form extracted from scrapie brain is protease resistant (PrP-res), whereas PrP from normal brain is protease sensitive (PrP-sen). This study examined whether PrP-res could be detected in brains of sheep with scrapie by immunohistochemistry (IHC). A suitable IHC procedure was developed using brain tissue from hamsters that had been inoculated with the transmissible mink encephalopathy agent. Tissue samples were fixed in PLP (periodate, lysine, paraformaldehyde) that contained paraformaldehyde at a concentration of 0.125%. Before application of the IHC technique, tissue sections were deparaffinized and treated with formic acid to simultaneously enhance PrP-res immunoreactivity and degrade PrP-sen. Primary antibody was obtained from a rabbit immunized to PrP-res extracted from brains of mice with experimentally induced scrapie. Brains from 21 sheep with histopathologically confirmed scrapie were examined by IHC. In all 21 brains, PrP-res was widely distributed throughout the brain stem. Staining was particularly intense in neuronal cell bodies and around blood vessels. The IHC technique successfully detected PrP-res in brain samples that had been frozen or that were severely autolyzed before fixation in PLP. Brains from 11 scrapie-suspect sheep that were not considered histologically positive were also examined by IHC. PrP-res was found in 4 of these brains. Sections of brains from 14 clinically normal sheep did not have detectable PrP-res. Results of this study indicate that IHC detection of PrP-res is equivalent, and perhaps superior, to histopathology for the diagnosis of scrapie in sheep. Furthermore, IHC is applicable to tissues that have autolytic changes or processing artifacts that prevent satisfactory histopathologic evaluation for lesions of scrapie.

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2020 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Prion diseases are a group of fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. In this study, we investigated the effects of baicalein on the development of prion diseases. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

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