The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Sanford L Boye - One of the best experts on this subject based on the ideXlab platform.
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sarm1 depletion rescues nmnat1 dependent Photoreceptor Cell death and retinal degeneration
eLife, 2020Co-Authors: Yo Sasaki, Hiroki Kakita, Shunsuke Kubota, Abdoulaye Sene, Tae Jun Lee, Norimitsu Ban, Zhenyu Dong, Joseph Lin, Sanford L BoyeAbstract:Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of Photoreceptors highlighting the exquisite vulnerability of these Cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the Photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger Photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in Photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and Photoreceptor neurodegeneration. These results define a novel SARM1-dependent Photoreceptor Cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.
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sarm1 depletion rescues nmnat1 dependent Photoreceptor Cell death and retinal degeneration
bioRxiv, 2020Co-Authors: Yo Sasaki, Hiroki Kakita, Shunsuke Kubota, Abdoulaye Sene, Tae Jun Lee, Norimitsu Ban, Zhenyu Dong, Joseph Lin, Sanford L BoyeAbstract:Abstract Leber congenital amaurosis type 9 (LCA9) is an autosomal recessive, early onset retinal neurodegenerative disease caused by mutations in the gene encoding the nuclear NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1 and its role in NAD+ homeostasis, LCA9 patients do not manifest pathologies other than retinal degeneration. To investigate the mechanism of degeneration, we examined retinas of developing and adult mice with conditional or tissue-specific NMNAT1 loss. Widespread NMNAT1 depletion in adult mice resulted in loss of Photoreceptors, indicating these Cells are exquisitely vulnerable to NMNAT1 loss. NMNAT1 is required within the Photoreceptor, as conditional deletion of NMNAT1 in Photoreceptors but not retinal pigment epithelial Cells is sufficient to cause Photoreceptor neurodegeneration and vision loss. Moreover, delivery of NMNAT1 into eyes of adult mice lacking NMNAT1 using a modified AAV8 vector containing a Photoreceptor-specific promoter rescued the retinal degeneration phenotype and partially restored vision. Finally, we defined the molecular mechanism driving Photoreceptor Cell death. Loss of NMNAT1 activates SARM1, an inducible NADase best known as the central executioner of axon degeneration. SARM1 is required for the Photoreceptor death and vision loss that occurs following NMNAT1 deletion. This surprising finding demonstrates that the essential function of NMNAT1 in Photoreceptors is to inhibit SARM1, and establishes a commonality of mechanism between axonal degeneration and Photoreceptor neurodegeneration. These results define a novel SARM1-dependent Photoreceptor Cell death pathway that is active in the setting of dysregulated NAD+ metabolism and identifies SARM1 as a therapeutic candidate for the treatment of retinal degeneration.
Hiroki Kakita - One of the best experts on this subject based on the ideXlab platform.
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sarm1 depletion rescues nmnat1 dependent Photoreceptor Cell death and retinal degeneration
eLife, 2020Co-Authors: Yo Sasaki, Hiroki Kakita, Shunsuke Kubota, Abdoulaye Sene, Tae Jun Lee, Norimitsu Ban, Zhenyu Dong, Joseph Lin, Sanford L BoyeAbstract:Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of Photoreceptors highlighting the exquisite vulnerability of these Cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the Photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger Photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in Photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and Photoreceptor neurodegeneration. These results define a novel SARM1-dependent Photoreceptor Cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.
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sarm1 depletion rescues nmnat1 dependent Photoreceptor Cell death and retinal degeneration
bioRxiv, 2020Co-Authors: Yo Sasaki, Hiroki Kakita, Shunsuke Kubota, Abdoulaye Sene, Tae Jun Lee, Norimitsu Ban, Zhenyu Dong, Joseph Lin, Sanford L BoyeAbstract:Abstract Leber congenital amaurosis type 9 (LCA9) is an autosomal recessive, early onset retinal neurodegenerative disease caused by mutations in the gene encoding the nuclear NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1 and its role in NAD+ homeostasis, LCA9 patients do not manifest pathologies other than retinal degeneration. To investigate the mechanism of degeneration, we examined retinas of developing and adult mice with conditional or tissue-specific NMNAT1 loss. Widespread NMNAT1 depletion in adult mice resulted in loss of Photoreceptors, indicating these Cells are exquisitely vulnerable to NMNAT1 loss. NMNAT1 is required within the Photoreceptor, as conditional deletion of NMNAT1 in Photoreceptors but not retinal pigment epithelial Cells is sufficient to cause Photoreceptor neurodegeneration and vision loss. Moreover, delivery of NMNAT1 into eyes of adult mice lacking NMNAT1 using a modified AAV8 vector containing a Photoreceptor-specific promoter rescued the retinal degeneration phenotype and partially restored vision. Finally, we defined the molecular mechanism driving Photoreceptor Cell death. Loss of NMNAT1 activates SARM1, an inducible NADase best known as the central executioner of axon degeneration. SARM1 is required for the Photoreceptor death and vision loss that occurs following NMNAT1 deletion. This surprising finding demonstrates that the essential function of NMNAT1 in Photoreceptors is to inhibit SARM1, and establishes a commonality of mechanism between axonal degeneration and Photoreceptor neurodegeneration. These results define a novel SARM1-dependent Photoreceptor Cell death pathway that is active in the setting of dysregulated NAD+ metabolism and identifies SARM1 as a therapeutic candidate for the treatment of retinal degeneration.
Keiko Kataoka - One of the best experts on this subject based on the ideXlab platform.
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Effects of BNN27, a novel C17-spiroepoxy steroid derivative, on experimental retinal detachment-induced Photoreceptor Cell death.
Scientific reports, 2018Co-Authors: Pavlina Tsoka, Demetrios G. Vavvas, Hidetaka Matsumoto, Keiko Kataoka, Daniel E. Maidana, I. Naoumidi, Achille Gravanis, Miltiadis K. TsilimbarisAbstract:Retinal detachment (RD) leads to Photoreceptor Cell death secondary to the physical separation of the retina from the underlying retinal pigment epithelium. Intensifying Photoreceptor survival in the detached retina could be remarkably favorable for many retinopathies in which RD can be seen. BNN27, a blood-brain barrier (BBB)-permeable, C17-spiroepoxy derivative of dehydroepiandrosterone (DHEA) has shown promising neuroprotective activity through interaction with nerve growth factor receptors, TrkA and p75NTR. Here, we administered BNN27 systemically in a murine model of RD. TUNEL+ Photoreceptors were significantly decreased 24 hours post injury after a single administration of 200 mg/kg BNN27. Furthermore, BNN27 increased inflammatory Cell infiltration, as well as, two markers of gliosis 24 hours post RD. However, single or multiple doses of BNN27 were not able to protect the overall survival of Photoreceptors 7 days post injury. Additionally, BNN27 did not induce the activation/phosphorylation of TrkAY490 in the detached retina although the mRNA levels of the receptor were increased in the Photoreceptors post injury. Together, these findings, do not demonstrate neuroprotective activity of BNN27 in experimentally-induced RD. Further studies are needed in order to elucidate the paradox/contradiction of these results and the mechanism of action of BNN27 in this model of Photoreceptor Cell damage.
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macrophage and rip3 dependent inflammasome activation exacerbates retinal detachment induced Photoreceptor Cell death
Cell Death and Disease, 2015Co-Authors: Yusuke Murakami, Hidetaka Matsumoto, Keiko Kataoka, Shoji Notomi, Hiroki Kaneko, Kimio Takeuchi, J H Sweigard, Alp Atik, Kip M. ConnorAbstract:Detachment of Photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in Photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal Cell death. Moreover, the Cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with Photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1β, an end product of inflammasome activation. In an animal model of RD, Photoreceptor Cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying Photoreceptors. Inflammasome inhibition attenuated Photoreceptor death after RD. Our data implicate the infiltrating macrophages as a source of damaging inflammasomes after Photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases.
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mammalian ste20 like kinase 2 not kinase 1 mediates Photoreceptor Cell death during retinal detachment
Cell Death and Disease, 2014Co-Authors: Hidetaka Matsumoto, Yusuke Murakami, Joan W. Miller, Keiko Kataoka, Kip M. Connor, Haijiang Lin, Dawang Zhou, Joseph Avruch, Demetrios G. VavvasAbstract:Photoreceptor Cell death is the definitive cause of vision loss in retinal detachment (RD). Mammalian STE20-like kinase (MST) is a master regulator of both Cell death and proliferation and a critical factor in development and tumorigenesis. However, to date the role of MST in neurodegeneration has not been fully explored. Utilizing MST1−/− and MST2−/− mice we identified MST2, but not MST1, as a regulator of Photoreceptor Cell death in a mouse model of RD. MST2−/− mice demonstrated significantly decreased Photoreceptor Cell death and outer nuclear layer (ONL) thinning after RD. Additionally, caspase-3 activation was attenuated in MST2−/− mice compared to control mice after RD. The transcription of p53 upregulated modulator of apoptosis (PUMA) and Fas was also reduced in MST2−/− mice post-RD. Retinas of MST2−/− mice displayed suppressed nuclear relocalization of phosphorylated YAP after RD. Consistent with the reduction of Photoreceptor Cell death, MST2−/− mice showed decreased levels of proinflammatory cytokines such as monocyte chemoattractant protein 1 and interleukin 6 as well as attenuated inflammatory CD11b Cell infiltration during the early phase of RD. These results identify MST2, not MST1, as a critical regulator of caspase-mediated Photoreceptor Cell death in the detached retina and indicate its potential as a future neuroprotection target.
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Strain Difference in Photoreceptor Cell Death After Retinal Detachment in Mice
Investigative ophthalmology & visual science, 2014Co-Authors: Hidetaka Matsumoto, Joan W. Miller, Keiko Kataoka, Pavlina Tsoka, Kip M. Connor, Demetrios G. VavvasAbstract:Purpose. To evaluate the potential for mouse genetic background to effect Photoreceptor Cell death in response to experimental retinal detachment (RD).
Hidetaka Matsumoto - One of the best experts on this subject based on the ideXlab platform.
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Effects of BNN27, a novel C17-spiroepoxy steroid derivative, on experimental retinal detachment-induced Photoreceptor Cell death.
Scientific reports, 2018Co-Authors: Pavlina Tsoka, Demetrios G. Vavvas, Hidetaka Matsumoto, Keiko Kataoka, Daniel E. Maidana, I. Naoumidi, Achille Gravanis, Miltiadis K. TsilimbarisAbstract:Retinal detachment (RD) leads to Photoreceptor Cell death secondary to the physical separation of the retina from the underlying retinal pigment epithelium. Intensifying Photoreceptor survival in the detached retina could be remarkably favorable for many retinopathies in which RD can be seen. BNN27, a blood-brain barrier (BBB)-permeable, C17-spiroepoxy derivative of dehydroepiandrosterone (DHEA) has shown promising neuroprotective activity through interaction with nerve growth factor receptors, TrkA and p75NTR. Here, we administered BNN27 systemically in a murine model of RD. TUNEL+ Photoreceptors were significantly decreased 24 hours post injury after a single administration of 200 mg/kg BNN27. Furthermore, BNN27 increased inflammatory Cell infiltration, as well as, two markers of gliosis 24 hours post RD. However, single or multiple doses of BNN27 were not able to protect the overall survival of Photoreceptors 7 days post injury. Additionally, BNN27 did not induce the activation/phosphorylation of TrkAY490 in the detached retina although the mRNA levels of the receptor were increased in the Photoreceptors post injury. Together, these findings, do not demonstrate neuroprotective activity of BNN27 in experimentally-induced RD. Further studies are needed in order to elucidate the paradox/contradiction of these results and the mechanism of action of BNN27 in this model of Photoreceptor Cell damage.
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macrophage and rip3 dependent inflammasome activation exacerbates retinal detachment induced Photoreceptor Cell death
Cell Death and Disease, 2015Co-Authors: Yusuke Murakami, Hidetaka Matsumoto, Keiko Kataoka, Shoji Notomi, Hiroki Kaneko, Kimio Takeuchi, J H Sweigard, Alp Atik, Kip M. ConnorAbstract:Detachment of Photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in Photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal Cell death. Moreover, the Cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with Photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1β, an end product of inflammasome activation. In an animal model of RD, Photoreceptor Cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying Photoreceptors. Inflammasome inhibition attenuated Photoreceptor death after RD. Our data implicate the infiltrating macrophages as a source of damaging inflammasomes after Photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases.
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mammalian ste20 like kinase 2 not kinase 1 mediates Photoreceptor Cell death during retinal detachment
Cell Death and Disease, 2014Co-Authors: Hidetaka Matsumoto, Yusuke Murakami, Joan W. Miller, Keiko Kataoka, Kip M. Connor, Haijiang Lin, Dawang Zhou, Joseph Avruch, Demetrios G. VavvasAbstract:Photoreceptor Cell death is the definitive cause of vision loss in retinal detachment (RD). Mammalian STE20-like kinase (MST) is a master regulator of both Cell death and proliferation and a critical factor in development and tumorigenesis. However, to date the role of MST in neurodegeneration has not been fully explored. Utilizing MST1−/− and MST2−/− mice we identified MST2, but not MST1, as a regulator of Photoreceptor Cell death in a mouse model of RD. MST2−/− mice demonstrated significantly decreased Photoreceptor Cell death and outer nuclear layer (ONL) thinning after RD. Additionally, caspase-3 activation was attenuated in MST2−/− mice compared to control mice after RD. The transcription of p53 upregulated modulator of apoptosis (PUMA) and Fas was also reduced in MST2−/− mice post-RD. Retinas of MST2−/− mice displayed suppressed nuclear relocalization of phosphorylated YAP after RD. Consistent with the reduction of Photoreceptor Cell death, MST2−/− mice showed decreased levels of proinflammatory cytokines such as monocyte chemoattractant protein 1 and interleukin 6 as well as attenuated inflammatory CD11b Cell infiltration during the early phase of RD. These results identify MST2, not MST1, as a critical regulator of caspase-mediated Photoreceptor Cell death in the detached retina and indicate its potential as a future neuroprotection target.
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Strain Difference in Photoreceptor Cell Death After Retinal Detachment in Mice
Investigative ophthalmology & visual science, 2014Co-Authors: Hidetaka Matsumoto, Joan W. Miller, Keiko Kataoka, Pavlina Tsoka, Kip M. Connor, Demetrios G. VavvasAbstract:Purpose. To evaluate the potential for mouse genetic background to effect Photoreceptor Cell death in response to experimental retinal detachment (RD).
Yo Sasaki - One of the best experts on this subject based on the ideXlab platform.
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sarm1 depletion rescues nmnat1 dependent Photoreceptor Cell death and retinal degeneration
eLife, 2020Co-Authors: Yo Sasaki, Hiroki Kakita, Shunsuke Kubota, Abdoulaye Sene, Tae Jun Lee, Norimitsu Ban, Zhenyu Dong, Joseph Lin, Sanford L BoyeAbstract:Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of Photoreceptors highlighting the exquisite vulnerability of these Cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the Photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger Photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in Photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and Photoreceptor neurodegeneration. These results define a novel SARM1-dependent Photoreceptor Cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.
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sarm1 depletion rescues nmnat1 dependent Photoreceptor Cell death and retinal degeneration
bioRxiv, 2020Co-Authors: Yo Sasaki, Hiroki Kakita, Shunsuke Kubota, Abdoulaye Sene, Tae Jun Lee, Norimitsu Ban, Zhenyu Dong, Joseph Lin, Sanford L BoyeAbstract:Abstract Leber congenital amaurosis type 9 (LCA9) is an autosomal recessive, early onset retinal neurodegenerative disease caused by mutations in the gene encoding the nuclear NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1 and its role in NAD+ homeostasis, LCA9 patients do not manifest pathologies other than retinal degeneration. To investigate the mechanism of degeneration, we examined retinas of developing and adult mice with conditional or tissue-specific NMNAT1 loss. Widespread NMNAT1 depletion in adult mice resulted in loss of Photoreceptors, indicating these Cells are exquisitely vulnerable to NMNAT1 loss. NMNAT1 is required within the Photoreceptor, as conditional deletion of NMNAT1 in Photoreceptors but not retinal pigment epithelial Cells is sufficient to cause Photoreceptor neurodegeneration and vision loss. Moreover, delivery of NMNAT1 into eyes of adult mice lacking NMNAT1 using a modified AAV8 vector containing a Photoreceptor-specific promoter rescued the retinal degeneration phenotype and partially restored vision. Finally, we defined the molecular mechanism driving Photoreceptor Cell death. Loss of NMNAT1 activates SARM1, an inducible NADase best known as the central executioner of axon degeneration. SARM1 is required for the Photoreceptor death and vision loss that occurs following NMNAT1 deletion. This surprising finding demonstrates that the essential function of NMNAT1 in Photoreceptors is to inhibit SARM1, and establishes a commonality of mechanism between axonal degeneration and Photoreceptor neurodegeneration. These results define a novel SARM1-dependent Photoreceptor Cell death pathway that is active in the setting of dysregulated NAD+ metabolism and identifies SARM1 as a therapeutic candidate for the treatment of retinal degeneration.