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José M. Izquierdo - One of the best experts on this subject based on the ideXlab platform.
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Transcriptome-wide analysis links the short-term expression of the b isoforms of TIA proteins to protective proteostasis-mediated cell quiescence response.
PloS one, 2018Co-Authors: Isabel Carrascoso, José Alcalde, Daniel Tabas-madrid, Juan Carlos Oliveros, José M. IzquierdoAbstract:Control of gene expression depends on genetics and environmental factors. The T-cell intracellular antigens T-cell intracellular antigen 1 (TIA1), TIA1-like/related protein (TIAL1/TIAR) and human antigen R (HuR/ELAVL1) are RNA-binding proteins that play crucial roles in regulating gene expression in both situations. This study used massive sequencing analysis to uncover molecular and functional mechanisms resulting from the short-time expression of the b isoforms of TIA1 and TIAR, and of HuR in HEK293 cells. Our gene profiling analysis identified several hundred differentially expressed genes (DEGs) and tens of alternative splicing events associated with TIA1b, TIARb and HuR overexpression. Gene ontology analysis revealed that the controlled expression of these proteins strongly influences the patterns of DEGs and RNA variants preferentially associated with development, reproduction, cell cycle, metabolism, autophagy and apoptosis. Mechanistically, TIA1b and TIARb isoforms display both common and differential effects on the regulation of gene expression, involving systematic perturbations of cell biosynthetic machineries (splicing and translation). The transcriptome outputs were validated using functional assays of the targeted cellular processes as well as expression analysis for selected genes. Collectively, our observations suggest that early TIA1b and TIARb expression operates to connect the regulatory crossroads to protective proteostasis responses associated with a survival quiescence phenotype.
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a heterologous cell model for studying the role of t cell intracellular antigen 1 in welander distal myopathy
Molecular and Cellular Biology, 2018Co-Authors: Isabel Carrascoso, José Alcalde, Carmen Sanchezjimenez, Elena Silion, José M. IzquierdoAbstract:: Welander distal myopathy (WDM) is a muscle dystrophy characterized by adult-onset distal muscle weakness, prevalently impacting the distal long extensors of the hands and feet. WDM is an autosomal dominant disorder caused by a missense mutation (c.1362G>A; p.E384K) in the TIA1 (T-cell intracellular antigen 1) gene, which encodes an RNA-binding protein basically required for the posttranscriptional regulation of RNAs. We have developed a heterologous cell model of WDM to study the molecular and cellular events associated with mutated TIA1 expression. Specifically, we analyzed how this mutation affects three regulatory functions mediated by TIA1: (i) control of alternative SMN2 (survival motor neuron 2) splicing; (ii) formation, assembly, and disassembly of stress granules; and (iii) mitochondrial dynamics and its consequences for mitophagy, autophagy, and apoptosis. Our results show that whereas WDM-associated TIA1 expression had only a mild effect on SMN2 splicing, it led to suboptimal adaptation to environmental stress, with exacerbated stress granule formation that was accompanied by mitochondrial dysfunction and autophagy. Overall, our observations indicate that some aspects of the cell phenotype seen in muscle of patients with WDM can be recapitulated by ectopic expression of WDM-TIA1 in embryonic kidney cells, highlighting the potential of this model to investigate the pathogenesis of this degenerative disease and possible therapeutics.
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T-cell intracellular antigens in health and disease
Cell cycle (Georgetown Tex.), 2015Co-Authors: Carmen Sánchez-jiménez, José M. IzquierdoAbstract:T-cell intracellular antigen 1 (TIA1) and TIA1-related/like protein (TIAR/TIAL1) are 2 proteins discovered in 1991 as components of cytotoxic T lymphocyte granules. They act in the nucleus as regulators of transcription and pre-mRNA splicing. In the cytoplasm, TIA1 and TIAR regulate and/or modulate the location, stability and/or translation of mRNAs. As knowledge of the different genes regulated by these proteins and the cellular/biological programs in which they are involved increases, it is evident that these antigens are key players in human physiology and pathology. This review will discuss the latest developments in the field, with physiopathological relevance, that point to novel roles for these regulators in the molecular and cell biology of higher eukaryotes.
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Long-Term Reduction of T-Cell Intracellular Antigens Reveals a Transcriptome Associated with Extracellular Matrix and Cell Adhesion Components
PLoS ONE, 2014Co-Authors: Mario Núñez, José Alcalde, Carmen Sánchez-jiménez, José M. IzquierdoAbstract:Knockdown of T-cell intracellular antigens TIA1 and TIAR contributes to a cellular phenotype characterised by uncontrolled proliferation and tumorigenesis. Massive-scale poly(A+) RNA sequencing of TIA1 or TIAR-knocked down HeLa cells reveals transcriptome signatures comprising genes and functional categories potentially able to modulate several aspects of membrane dynamics associated with extracellular matrix and focal/cell adhesion events. The transcriptomic heterogeneity is the result of differentially expressed genes and RNA isoforms generated by alternative splicing and/or promoter usage. These results suggest a role for TIA proteins in the regulation and/or modulation of cellular homeostasis related to focal/cell adhesion, extracellular matrix and membrane and cytoskeleton dynamics.
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Long-term reduction of T-cell intracellular antigens leads to increased beta-actin expression
Molecular cancer, 2014Co-Authors: Isabel Carrascoso, Carmen Sánchez-jiménez, José M. IzquierdoAbstract:The permanent down-regulated expression of T-cell intracellular antigen (TIA) proteins in HeLa cells improves cytoskeleton-mediated functions such as cell proliferation and tumor growth. Making use of human and mouse cells with knocked down/out expression of T-cell intracellular antigen 1 (TIA1) and/or TIA1 related/like (TIAR/TIAL1) proteins and classical RNA (e.g. reverse transcription-quantitative polymerase chain reaction, polysomal profiling analysis using sucrose gradients, immunoblotting, immunoprecipitation, electrophoretic mobility shift assays, ultraviolet light crosslinking and poly (A+) test analysis) and cellular (e.g. immunofluorescence microscopy and quimeric mRNA transfections) biology methods, we have analyzed the regulatory role of TIA proteins in the post-transcriptional modulation of beta-actin (ACTB) mRNA. Our observations show that the acquisition of above cellular capacities is concomitant with increased expression levels of the actin beta subunit (ACTB) protein. Regulating TIA abundance does not modify ACTB mRNA levels, however, an increase of ACTB mRNA translation is observed. This regulatory capacity of TIA proteins is linked to the ACTB mRNA 3′-untranslated region (3′-UTR), where these proteins could function as RNA binding proteins. The expression of GFP from a chimeric reporter containing human ΑCΤΒ 3′-UTR recapitulates the translational control found by the endogenous ACTB mRNA in the absence of TIA proteins. Additionally, murine embryonic fibroblasts (MEF) knocked out for TIA1 rise mouse ACTB protein expression compared to the controls. Once again steady-state levels of mouse ACTB mRNA remained unchanged. Collectively, these results suggest that TIA proteins can function as long-term regulators of the ACTB mRNA metabolism in mouse and human cells.
Isabel Carrascoso - One of the best experts on this subject based on the ideXlab platform.
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Transcriptome-wide analysis links the short-term expression of the b isoforms of TIA proteins to protective proteostasis-mediated cell quiescence response.
PloS one, 2018Co-Authors: Isabel Carrascoso, José Alcalde, Daniel Tabas-madrid, Juan Carlos Oliveros, José M. IzquierdoAbstract:Control of gene expression depends on genetics and environmental factors. The T-cell intracellular antigens T-cell intracellular antigen 1 (TIA1), TIA1-like/related protein (TIAL1/TIAR) and human antigen R (HuR/ELAVL1) are RNA-binding proteins that play crucial roles in regulating gene expression in both situations. This study used massive sequencing analysis to uncover molecular and functional mechanisms resulting from the short-time expression of the b isoforms of TIA1 and TIAR, and of HuR in HEK293 cells. Our gene profiling analysis identified several hundred differentially expressed genes (DEGs) and tens of alternative splicing events associated with TIA1b, TIARb and HuR overexpression. Gene ontology analysis revealed that the controlled expression of these proteins strongly influences the patterns of DEGs and RNA variants preferentially associated with development, reproduction, cell cycle, metabolism, autophagy and apoptosis. Mechanistically, TIA1b and TIARb isoforms display both common and differential effects on the regulation of gene expression, involving systematic perturbations of cell biosynthetic machineries (splicing and translation). The transcriptome outputs were validated using functional assays of the targeted cellular processes as well as expression analysis for selected genes. Collectively, our observations suggest that early TIA1b and TIARb expression operates to connect the regulatory crossroads to protective proteostasis responses associated with a survival quiescence phenotype.
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a heterologous cell model for studying the role of t cell intracellular antigen 1 in welander distal myopathy
Molecular and Cellular Biology, 2018Co-Authors: Isabel Carrascoso, José Alcalde, Carmen Sanchezjimenez, Elena Silion, José M. IzquierdoAbstract:: Welander distal myopathy (WDM) is a muscle dystrophy characterized by adult-onset distal muscle weakness, prevalently impacting the distal long extensors of the hands and feet. WDM is an autosomal dominant disorder caused by a missense mutation (c.1362G>A; p.E384K) in the TIA1 (T-cell intracellular antigen 1) gene, which encodes an RNA-binding protein basically required for the posttranscriptional regulation of RNAs. We have developed a heterologous cell model of WDM to study the molecular and cellular events associated with mutated TIA1 expression. Specifically, we analyzed how this mutation affects three regulatory functions mediated by TIA1: (i) control of alternative SMN2 (survival motor neuron 2) splicing; (ii) formation, assembly, and disassembly of stress granules; and (iii) mitochondrial dynamics and its consequences for mitophagy, autophagy, and apoptosis. Our results show that whereas WDM-associated TIA1 expression had only a mild effect on SMN2 splicing, it led to suboptimal adaptation to environmental stress, with exacerbated stress granule formation that was accompanied by mitochondrial dysfunction and autophagy. Overall, our observations indicate that some aspects of the cell phenotype seen in muscle of patients with WDM can be recapitulated by ectopic expression of WDM-TIA1 in embryonic kidney cells, highlighting the potential of this model to investigate the pathogenesis of this degenerative disease and possible therapeutics.
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Long-term reduction of T-cell intracellular antigens leads to increased beta-actin expression
Molecular cancer, 2014Co-Authors: Isabel Carrascoso, Carmen Sánchez-jiménez, José M. IzquierdoAbstract:The permanent down-regulated expression of T-cell intracellular antigen (TIA) proteins in HeLa cells improves cytoskeleton-mediated functions such as cell proliferation and tumor growth. Making use of human and mouse cells with knocked down/out expression of T-cell intracellular antigen 1 (TIA1) and/or TIA1 related/like (TIAR/TIAL1) proteins and classical RNA (e.g. reverse transcription-quantitative polymerase chain reaction, polysomal profiling analysis using sucrose gradients, immunoblotting, immunoprecipitation, electrophoretic mobility shift assays, ultraviolet light crosslinking and poly (A+) test analysis) and cellular (e.g. immunofluorescence microscopy and quimeric mRNA transfections) biology methods, we have analyzed the regulatory role of TIA proteins in the post-transcriptional modulation of beta-actin (ACTB) mRNA. Our observations show that the acquisition of above cellular capacities is concomitant with increased expression levels of the actin beta subunit (ACTB) protein. Regulating TIA abundance does not modify ACTB mRNA levels, however, an increase of ACTB mRNA translation is observed. This regulatory capacity of TIA proteins is linked to the ACTB mRNA 3′-untranslated region (3′-UTR), where these proteins could function as RNA binding proteins. The expression of GFP from a chimeric reporter containing human ΑCΤΒ 3′-UTR recapitulates the translational control found by the endogenous ACTB mRNA in the absence of TIA proteins. Additionally, murine embryonic fibroblasts (MEF) knocked out for TIA1 rise mouse ACTB protein expression compared to the controls. Once again steady-state levels of mouse ACTB mRNA remained unchanged. Collectively, these results suggest that TIA proteins can function as long-term regulators of the ACTB mRNA metabolism in mouse and human cells.
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Knockdown of T-cell intracellular antigens triggers cell proliferation, invasion and tumour growth.
The Biochemical journal, 2011Co-Authors: José M. Izquierdo, Isabel Carrascoso, José Alcalde, Raquel Reyes, María Dolores LudeñaAbstract:TIA (T-cell intracellular antigen) proteins function as DNA/RNA trans-acting regulators to expand transcriptome and proteome diversity in mammals. In the present paper we report that the stable silencing of TIA1 and/or TIAR/TIAL1 (TIA1-related/like protein 1) expression in HeLa cells enhances cell proliferation, anchorage-dependent and -independent growth and invasion. HeLa cells lacking TIA1 and/or TIAR generate larger and faster-growing epithelial tumours with high rates of proliferation and angiogenesis in nude mice xenografts. Protein array analysis of a collection of human tumours shows that TIA1 and TIAR protein expression is down-regulated in a subset of epithelial tumours relative to normal tissues. Our results suggest a link between the epigenetic control exerted by TIA proteins and the transcriptional and post-transcriptional regulation of a subset of specific genes involved in tumour progression. Taken together, these results are consistent with a role for TIA proteins as growth/tumour-suppressor genes.
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Knockdown of T-cell intracellular antigens triggers cell proliferation, invasion and tumor growth.
Biochemical Journal, 2011Co-Authors: José M. Izquierdo, Isabel Carrascoso, José Alcalde, Raquel Reyes, María Dolores LudeñaAbstract:T-cell intracellular antigen (TIA) proteins function as DNA/RNA trans-acting regulators to expand transcriptome and proteome diversity in mammals. We hereby report that stable silencing of TIA1 and/or TIAR/TIAL1 expression in HeLa cells enhances cell proliferation, anchorage-dependent and -independent growth and invasion. HeLa cells lacking TIA1 and/or TIAR generate larger and faster-growing epithelial tumors with high rates of proliferation and angiogenesis in nude mice xenografts. Protein array analysis of a collection of human tumors shows that TIA1 and TIAR protein expression is downregulated in a subset of epithelial tumors relative to normal tissues. Our data suggest a link between the epigenetic control exerted by TIA proteins on transcriptional and post-transcriptional regulation of a subset of specific gene involved in tumor progression. Taken together, these results are consistent with a role for TIA proteins as growth/tumor suppressor genes.
José Alcalde - One of the best experts on this subject based on the ideXlab platform.
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Transcriptome-wide analysis links the short-term expression of the b isoforms of TIA proteins to protective proteostasis-mediated cell quiescence response.
PloS one, 2018Co-Authors: Isabel Carrascoso, José Alcalde, Daniel Tabas-madrid, Juan Carlos Oliveros, José M. IzquierdoAbstract:Control of gene expression depends on genetics and environmental factors. The T-cell intracellular antigens T-cell intracellular antigen 1 (TIA1), TIA1-like/related protein (TIAL1/TIAR) and human antigen R (HuR/ELAVL1) are RNA-binding proteins that play crucial roles in regulating gene expression in both situations. This study used massive sequencing analysis to uncover molecular and functional mechanisms resulting from the short-time expression of the b isoforms of TIA1 and TIAR, and of HuR in HEK293 cells. Our gene profiling analysis identified several hundred differentially expressed genes (DEGs) and tens of alternative splicing events associated with TIA1b, TIARb and HuR overexpression. Gene ontology analysis revealed that the controlled expression of these proteins strongly influences the patterns of DEGs and RNA variants preferentially associated with development, reproduction, cell cycle, metabolism, autophagy and apoptosis. Mechanistically, TIA1b and TIARb isoforms display both common and differential effects on the regulation of gene expression, involving systematic perturbations of cell biosynthetic machineries (splicing and translation). The transcriptome outputs were validated using functional assays of the targeted cellular processes as well as expression analysis for selected genes. Collectively, our observations suggest that early TIA1b and TIARb expression operates to connect the regulatory crossroads to protective proteostasis responses associated with a survival quiescence phenotype.
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a heterologous cell model for studying the role of t cell intracellular antigen 1 in welander distal myopathy
Molecular and Cellular Biology, 2018Co-Authors: Isabel Carrascoso, José Alcalde, Carmen Sanchezjimenez, Elena Silion, José M. IzquierdoAbstract:: Welander distal myopathy (WDM) is a muscle dystrophy characterized by adult-onset distal muscle weakness, prevalently impacting the distal long extensors of the hands and feet. WDM is an autosomal dominant disorder caused by a missense mutation (c.1362G>A; p.E384K) in the TIA1 (T-cell intracellular antigen 1) gene, which encodes an RNA-binding protein basically required for the posttranscriptional regulation of RNAs. We have developed a heterologous cell model of WDM to study the molecular and cellular events associated with mutated TIA1 expression. Specifically, we analyzed how this mutation affects three regulatory functions mediated by TIA1: (i) control of alternative SMN2 (survival motor neuron 2) splicing; (ii) formation, assembly, and disassembly of stress granules; and (iii) mitochondrial dynamics and its consequences for mitophagy, autophagy, and apoptosis. Our results show that whereas WDM-associated TIA1 expression had only a mild effect on SMN2 splicing, it led to suboptimal adaptation to environmental stress, with exacerbated stress granule formation that was accompanied by mitochondrial dysfunction and autophagy. Overall, our observations indicate that some aspects of the cell phenotype seen in muscle of patients with WDM can be recapitulated by ectopic expression of WDM-TIA1 in embryonic kidney cells, highlighting the potential of this model to investigate the pathogenesis of this degenerative disease and possible therapeutics.
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Long-Term Reduction of T-Cell Intracellular Antigens Reveals a Transcriptome Associated with Extracellular Matrix and Cell Adhesion Components
PLoS ONE, 2014Co-Authors: Mario Núñez, José Alcalde, Carmen Sánchez-jiménez, José M. IzquierdoAbstract:Knockdown of T-cell intracellular antigens TIA1 and TIAR contributes to a cellular phenotype characterised by uncontrolled proliferation and tumorigenesis. Massive-scale poly(A+) RNA sequencing of TIA1 or TIAR-knocked down HeLa cells reveals transcriptome signatures comprising genes and functional categories potentially able to modulate several aspects of membrane dynamics associated with extracellular matrix and focal/cell adhesion events. The transcriptomic heterogeneity is the result of differentially expressed genes and RNA isoforms generated by alternative splicing and/or promoter usage. These results suggest a role for TIA proteins in the regulation and/or modulation of cellular homeostasis related to focal/cell adhesion, extracellular matrix and membrane and cytoskeleton dynamics.
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Knockdown of T-cell intracellular antigens triggers cell proliferation, invasion and tumour growth.
The Biochemical journal, 2011Co-Authors: José M. Izquierdo, Isabel Carrascoso, José Alcalde, Raquel Reyes, María Dolores LudeñaAbstract:TIA (T-cell intracellular antigen) proteins function as DNA/RNA trans-acting regulators to expand transcriptome and proteome diversity in mammals. In the present paper we report that the stable silencing of TIA1 and/or TIAR/TIAL1 (TIA1-related/like protein 1) expression in HeLa cells enhances cell proliferation, anchorage-dependent and -independent growth and invasion. HeLa cells lacking TIA1 and/or TIAR generate larger and faster-growing epithelial tumours with high rates of proliferation and angiogenesis in nude mice xenografts. Protein array analysis of a collection of human tumours shows that TIA1 and TIAR protein expression is down-regulated in a subset of epithelial tumours relative to normal tissues. Our results suggest a link between the epigenetic control exerted by TIA proteins and the transcriptional and post-transcriptional regulation of a subset of specific genes involved in tumour progression. Taken together, these results are consistent with a role for TIA proteins as growth/tumour-suppressor genes.
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Knockdown of T-cell intracellular antigens triggers cell proliferation, invasion and tumor growth.
Biochemical Journal, 2011Co-Authors: José M. Izquierdo, Isabel Carrascoso, José Alcalde, Raquel Reyes, María Dolores LudeñaAbstract:T-cell intracellular antigen (TIA) proteins function as DNA/RNA trans-acting regulators to expand transcriptome and proteome diversity in mammals. We hereby report that stable silencing of TIA1 and/or TIAR/TIAL1 expression in HeLa cells enhances cell proliferation, anchorage-dependent and -independent growth and invasion. HeLa cells lacking TIA1 and/or TIAR generate larger and faster-growing epithelial tumors with high rates of proliferation and angiogenesis in nude mice xenografts. Protein array analysis of a collection of human tumors shows that TIA1 and TIAR protein expression is downregulated in a subset of epithelial tumors relative to normal tissues. Our data suggest a link between the epigenetic control exerted by TIA proteins on transcriptional and post-transcriptional regulation of a subset of specific gene involved in tumor progression. Taken together, these results are consistent with a role for TIA proteins as growth/tumor suppressor genes.
Samantha Boudeau - One of the best experts on this subject based on the ideXlab platform.
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TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau.
Proceedings of the National Academy of Sciences of the United States of America, 2021Co-Authors: Peter E A Ash, Samantha Boudeau, Maria Medalla, Jenifer Shattuck, Shuwen Lei, Yari Carlomagno, Bryce L. Mashimo, Guillermo Socorro, Louloua F. A. Al-mohanna, Lulu JiangAbstract:Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities.
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Dysregulation of RNA Splicing in Tauopathies
Cell reports, 2019Co-Authors: Daniel J Apicco, Lulu Jiang, Brandon F. Maziuk, Heather I. Ballance, Samantha Boudeau, Cheng Zhang, Choong Ung, Benjamin WolozinAbstract:Pathological aggregation of RNA binding proteins (RBPs) is associated with dysregulation of RNA splicing in PS19 P301S tau transgenic mice and in Alzheimer's disease brain tissues. The dysregulated splicing particularly affects genes involved in synaptic transmission. The effects of neuroprotective TIA1 reduction on PS19 mice are also examined. TIA1 reduction reduces disease-linked alternative splicing events for the major synaptic mRNA transcripts examined, suggesting that normalization of RBP functions is associated with the neuroprotection. Use of the NetDecoder informatics algorithm identifies key upstream biological targets, including MYC and EGFR, underlying the transcriptional and splicing changes in the protected compared to tauopathy mice. Pharmacological inhibition of MYC and EGFR activity in neuronal cultures tau recapitulates the neuroprotective effects of TIA1 reduction. These results demonstrate that dysfunction of RBPs and RNA splicing processes are major elements of the pathophysiology of tauopathies, as well as potential therapeutic targets for tauopathies.
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TIA1 regulates the generation and response to toxic tau oligomers
Acta Neuropathologica, 2019Co-Authors: Lulu Jiang, Leonard Petrucelli, Brandon F. Maziuk, Heather I. Ballance, Samantha Boudeau, Ali Al Abdullatif, Marcello Orlando, Tsuneya Ikezu, Benjamin WolozinAbstract:RNA binding proteins (RBPs) are strongly linked to the pathophysiology of motor neuron diseases. Recent studies show that RBPs, such as TIA1, also contribute to the pathophysiology of tauopathy. RBPs co-localize with tau pathology, and reduction of TIA1 protects against tau-mediated neurodegeneration. The mechanism through which TIA1 reduction protects against tauopathy, and whether TIA1 modulates the propagation of tau, are unknown. Previous studies indicate that the protective effect of TIA1 depletion correlates with both the reduction of oligomeric tau and the reduction of pathological TIA1 positive tau inclusions. In the current report, we used a novel tau propagation approach to test whether TIA1 is required for producing toxic tau oligomers and whether TIA1 reduction would provide protection against the spread of these oligomers. The approach used young PS19 P301S tau mice at an age at which neurodegeneration would normally not yet occur and seeding oligomeric or fibrillar tau by injection into hippocampal CA1 region. We find that propagation of exogenous tau oligomers (but not fibrils) across the brain drives neurodegeneration in this model. We demonstrate that TIA1 reduction essentially brackets the pathophysiology of tau, being required for the production of tau oligomers, as well as regulating the response of neurons to propagated toxic tau oligomers. These results indicate that RNA binding proteins modulate the pathophysiology of tau at multiple levels and provide insights into possible therapeutic approaches to reduce the spread of neurodegeneration in tauopathy.
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Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo
Nature Neuroscience, 2018Co-Authors: Daniel J Apicco, Brandon F. Maziuk, Heather I. Ballance, Ali Al Abdullatif, Maria Medalla, Chelsey Leblang, Antonio Ferragud, Emily Botelho, Uma Dhawan, Samantha BoudeauAbstract:Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology. Apicco and colleagues show that reducing TIA1 inhibits tau-mediated neurodegeneration and improves survival in a mouse model of tauopathy. This rescue occurs with a transition in tau aggregation from oligomeric to fibrillar forms of tau. These findings suggest a key role for RNA binding proteins in the pathophysiology of tau.
Daniel J Apicco - One of the best experts on this subject based on the ideXlab platform.
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Dysregulation of RNA Splicing in Tauopathies
Cell reports, 2019Co-Authors: Daniel J Apicco, Lulu Jiang, Brandon F. Maziuk, Heather I. Ballance, Samantha Boudeau, Cheng Zhang, Choong Ung, Benjamin WolozinAbstract:Pathological aggregation of RNA binding proteins (RBPs) is associated with dysregulation of RNA splicing in PS19 P301S tau transgenic mice and in Alzheimer's disease brain tissues. The dysregulated splicing particularly affects genes involved in synaptic transmission. The effects of neuroprotective TIA1 reduction on PS19 mice are also examined. TIA1 reduction reduces disease-linked alternative splicing events for the major synaptic mRNA transcripts examined, suggesting that normalization of RBP functions is associated with the neuroprotection. Use of the NetDecoder informatics algorithm identifies key upstream biological targets, including MYC and EGFR, underlying the transcriptional and splicing changes in the protected compared to tauopathy mice. Pharmacological inhibition of MYC and EGFR activity in neuronal cultures tau recapitulates the neuroprotective effects of TIA1 reduction. These results demonstrate that dysfunction of RBPs and RNA splicing processes are major elements of the pathophysiology of tauopathies, as well as potential therapeutic targets for tauopathies.
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Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo
Nature Neuroscience, 2018Co-Authors: Daniel J Apicco, Brandon F. Maziuk, Heather I. Ballance, Ali Al Abdullatif, Maria Medalla, Chelsey Leblang, Antonio Ferragud, Emily Botelho, Uma Dhawan, Samantha BoudeauAbstract:Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology. Apicco and colleagues show that reducing TIA1 inhibits tau-mediated neurodegeneration and improves survival in a mouse model of tauopathy. This rescue occurs with a transition in tau aggregation from oligomeric to fibrillar forms of tau. These findings suggest a key role for RNA binding proteins in the pathophysiology of tau.
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reducing the rna binding protein TIA1 protects against tau mediated neurodegeneration in vivo
Nature Neuroscience, 2018Co-Authors: Daniel J Apicco, Brandon F. Maziuk, Heather I. Ballance, Ali Al Abdullatif, Maria Medalla, Peter E A Ash, Chelsey Leblang, Antonio Ferragud, Emily Botelho, Uma DhawanAbstract:Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.
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interaction of tau with the rna binding protein TIA1 regulates tau pathophysiology and toxicity
Cell Reports, 2016Co-Authors: Tara Vanderweyde, Daniel J Apicco, Katherine Youmanskidder, Peter E A Ash, Casey Cook, Edroaldo Lummertz Da Rocha, Karen Jansenwest, Alissa A Frame, Allison Citro, John D LeszykAbstract:Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while overexpressing TIA1 induces tau misfolding and stimulates neurodegeneration. Pharmacological interventions that prevent SG formation also inhibit tau pathophysiology. These studies suggest that the pathophysiology of tauopathy requires an intimate interaction with RNA-binding proteins.