Infection caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2)virus,responsible for the coronavirus disease 2019(COVID-19)pandemic,induces symptoms including increased inflammatory response,severe ...Infection caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2)virus,responsible for the coronavirus disease 2019(COVID-19)pandemic,induces symptoms including increased inflammatory response,severe acute respiratory syndrome(SARS),cognitive dysfunction like brain fog,and cardiovascular defects.Long-term effects of SARS-CoV2 COVID-19 syndrome referred to as post-COVID-19 syndrome on age-related progressive neurodegenerative disorders such as Alzheimer's disease remain understudied.Using the targeted misexpression of individual SARS-CoV2 proteins in the retinal neurons of the Drosophila melanogaster eye,we found that misexpression of nonstructural protein 3(Nsp3),a papain-like protease,ablates the eye and generates dark necrotic spots.Targeted misexpression of Nsp3 in the eye triggers reactive oxygen species production and leads to apoptosis as shown by cell death reporters,terminal deoxynucleotidyl transferase(TdT)dUTP Nick-end labeling(TUNEL)assay,and dihydroethidium staining.Furthermore,Nsp3 misexpression activates both apoptosis and autophagy mechanism(s)to regulate tissue homeostasis.Transient expression of SARS-CoV2 Nsp3 in murine neuroblastoma,Neuro-2a cells,significantly reduced the metabolic activity of these cells and triggers cell death.Misexpression of SARS-CoV2 Nsp3 in an Alzheimer's disease transgenic fly eye model(glass multiple repeats[GMR]>amyloidβ42)further enhances the neurodegenerative rough eye phenotype due to increased cell death.These findings suggest that SARS-CoV2 utilizes Nsp3 protein to potentiate cell death response in a neurodegenerative disease background that has high pre-existing levels of neuroinflammation and cell death.展开更多
During development,regulation of organ size requires a balance between cell proliferation,growth and cell death.Dysregulation of these fundamental processes can cause a variety of diseases.Excessive cell proliferation...During development,regulation of organ size requires a balance between cell proliferation,growth and cell death.Dysregulation of these fundamental processes can cause a variety of diseases.Excessive cell proliferation results in cancer whereas excessive cell death results in neurodegenerative disorders.Many signaling pathways known-to-date have a role in growth regulation.Among them,evolutionarily conserved Hippo signaling pathway is unique as it controls both cell proliferation and cell death by a variety of mechanisms during organ sculpture and development.Neurodegeneration,a complex process of progressive death of neuronal population,results in fatal disorders with no available cure to date.During normal development,cell death is required for sculpting of an organ.However,aberrant cell death in neuronal cell population can result in neurodegenerative disorders.Hippo pathway has gathered major attention for its role in growth regulation and cancer,however,other functions like its role in neurodegeneration are also emerging rapidly.This review highlights the role of Hippo signaling in cell death and neurodegenerative diseases and provide the information on the chemical inhibitors employed to block Hippo pathway.Understanding Hippo mediated cell death mechanisms will aid in development of reliable and effective therapeutic strategies in future.展开更多
Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivo...Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivotal to basic cellular processes.Close to 80%-90%of proteins are acetylated during translation,which is an irreversible process that affects protein structure,function,life,and localization.In this review,we have discussed the various N-acetyltransferases present in humans,their function,and how they might play a role in diseases.Furthermore,we have focused on N-acetyltransferase 9 and its role in microtubule stability.We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases.We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration.展开更多
基金supported by 1RO1EY032959-01 from NIHSchuellein Chair Endowment FundSTEM Catalyst Grant from the University of Dayton(all to AS)。
文摘Infection caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2)virus,responsible for the coronavirus disease 2019(COVID-19)pandemic,induces symptoms including increased inflammatory response,severe acute respiratory syndrome(SARS),cognitive dysfunction like brain fog,and cardiovascular defects.Long-term effects of SARS-CoV2 COVID-19 syndrome referred to as post-COVID-19 syndrome on age-related progressive neurodegenerative disorders such as Alzheimer's disease remain understudied.Using the targeted misexpression of individual SARS-CoV2 proteins in the retinal neurons of the Drosophila melanogaster eye,we found that misexpression of nonstructural protein 3(Nsp3),a papain-like protease,ablates the eye and generates dark necrotic spots.Targeted misexpression of Nsp3 in the eye triggers reactive oxygen species production and leads to apoptosis as shown by cell death reporters,terminal deoxynucleotidyl transferase(TdT)dUTP Nick-end labeling(TUNEL)assay,and dihydroethidium staining.Furthermore,Nsp3 misexpression activates both apoptosis and autophagy mechanism(s)to regulate tissue homeostasis.Transient expression of SARS-CoV2 Nsp3 in murine neuroblastoma,Neuro-2a cells,significantly reduced the metabolic activity of these cells and triggers cell death.Misexpression of SARS-CoV2 Nsp3 in an Alzheimer's disease transgenic fly eye model(glass multiple repeats[GMR]>amyloidβ42)further enhances the neurodegenerative rough eye phenotype due to increased cell death.These findings suggest that SARS-CoV2 utilizes Nsp3 protein to potentiate cell death response in a neurodegenerative disease background that has high pre-existing levels of neuroinflammation and cell death.
基金The authors are supported by the University of Dayton Graduate program of BiologyThis work was supported by NIH1R15GM124654-01 from the National Institutes of Health,Schuellein Chair Endowment Fund,and start-up support from the University of Dayton(to Amit S).
文摘During development,regulation of organ size requires a balance between cell proliferation,growth and cell death.Dysregulation of these fundamental processes can cause a variety of diseases.Excessive cell proliferation results in cancer whereas excessive cell death results in neurodegenerative disorders.Many signaling pathways known-to-date have a role in growth regulation.Among them,evolutionarily conserved Hippo signaling pathway is unique as it controls both cell proliferation and cell death by a variety of mechanisms during organ sculpture and development.Neurodegeneration,a complex process of progressive death of neuronal population,results in fatal disorders with no available cure to date.During normal development,cell death is required for sculpting of an organ.However,aberrant cell death in neuronal cell population can result in neurodegenerative disorders.Hippo pathway has gathered major attention for its role in growth regulation and cancer,however,other functions like its role in neurodegeneration are also emerging rapidly.This review highlights the role of Hippo signaling in cell death and neurodegenerative diseases and provide the information on the chemical inhibitors employed to block Hippo pathway.Understanding Hippo mediated cell death mechanisms will aid in development of reliable and effective therapeutic strategies in future.
基金supported by 1RO1EY032959-01 and RO1 supplement from NIH,Schuellein Chair Endowment Fund and STEM Catalyst Grant from the University of Dayton(to AS).
文摘Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivotal to basic cellular processes.Close to 80%-90%of proteins are acetylated during translation,which is an irreversible process that affects protein structure,function,life,and localization.In this review,we have discussed the various N-acetyltransferases present in humans,their function,and how they might play a role in diseases.Furthermore,we have focused on N-acetyltransferase 9 and its role in microtubule stability.We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases.We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration.
