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Stefan M. Pulst - One of the best experts on this subject based on the ideXlab platform.
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ALS-associated genes in SCA2 mouse spinal cord transcriptomes.
Human molecular genetics, 2020Co-Authors: Daniel R. Scoles, Karla P Figueroa, Lance Pflieger, Warunee Dansithong, Sharan Paul, Frank Rigo, Mandi Gandelman, C. Frank Bennett, Stefan M. PulstAbstract:The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration.
Nature communications, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Nature Communications, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2. Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
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Spinocerebellar ataxia type 2
Advances in experimental medicine and biology, 2018Co-Authors: Daniel R. Scoles, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is autosomal dominantly inherited and caused by CAG repeat expansion in the ATXN2 gene. Because the CAG repeat expansion is localized to an encoded region of ATXN2, the result is an expanded polyglutamine (polyQ) tract in the ATXN2 protein. SCA2 is characterized by progressive ataxia, and slow saccades. No treatment for SCA2 exists. ATXN2 mutation causes gains of new or toxic functions for the ATXN2 protein, resulting in abnormally slow Purkinje cell (PC) firing frequency and ultimately PC loss. This chapter describes the characteristics of SCA2 patients briefly, and reviews ATXN2 molecular features and progress toward the identification of a treatment for SCA2.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Nature Publishing Group, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2
Daniel R. Scoles - One of the best experts on this subject based on the ideXlab platform.
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ALS-associated genes in SCA2 mouse spinal cord transcriptomes.
Human molecular genetics, 2020Co-Authors: Daniel R. Scoles, Karla P Figueroa, Lance Pflieger, Warunee Dansithong, Sharan Paul, Frank Rigo, Mandi Gandelman, C. Frank Bennett, Stefan M. PulstAbstract:The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Nature Communications, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2. Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration.
Nature communications, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
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Spinocerebellar ataxia type 2
Advances in experimental medicine and biology, 2018Co-Authors: Daniel R. Scoles, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is autosomal dominantly inherited and caused by CAG repeat expansion in the ATXN2 gene. Because the CAG repeat expansion is localized to an encoded region of ATXN2, the result is an expanded polyglutamine (polyQ) tract in the ATXN2 protein. SCA2 is characterized by progressive ataxia, and slow saccades. No treatment for SCA2 exists. ATXN2 mutation causes gains of new or toxic functions for the ATXN2 protein, resulting in abnormally slow Purkinje cell (PC) firing frequency and ultimately PC loss. This chapter describes the characteristics of SCA2 patients briefly, and reviews ATXN2 molecular features and progress toward the identification of a treatment for SCA2.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Nature Publishing Group, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2
Susan W Liebman - One of the best experts on this subject based on the ideXlab platform.
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calcium responsive transactivator crest toxicity is rescued by loss of pbp1 ATXN2 function in a novel yeast proteinopathy model and in transgenic flies
PLOS Genetics, 2019Co-Authors: Sangeun Park, Seikyoung Park, Naruaki Watanabe, Tadafumi Hashimoto, Takeshi Iwatsubo, Tatyana A. Shelkovnikova, Susan W LiebmanAbstract:Proteins associated with familial neurodegenerative disease often aggregate in patients’ neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1, reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral sclerosis (ALS) risk factor and therapeutic target. Likewise, new yeast neurodegenerative disease models could facilitate identification of other risk factors and targets. Mutations in SS18L1, encoding the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS. We show that CREST is toxic in yeast and forms nuclear and occasionally cytoplasmic foci that stain with Thioflavin-T, a dye indicative of amyloid-like protein. Like the yeast chromatin-remodeling factor SWI1, CREST inhibits silencing of FLO genes. Toxicity of CREST is enhanced by the [PIN+] prion and reduced by deletion of the HSP104 chaperone required for the propagation of many yeast prions. Likewise, deletion of PBP1 reduced CREST toxicity and aggregation. In accord with the yeast data, we show that the Drosophila ortholog of human ATXN2, dAtx2, is a potent enhancer of CREST toxicity. Downregulation of dAtx2 in flies overexpressing CREST in retinal ganglion cells was sufficient to largely rescue the severe degenerative phenotype induced by human CREST. Overexpression caused considerable co-localization of CREST and PBP1/ATXN2 in cytoplasmic foci in both yeast and mammalian cells. Thus, co-aggregation of CREST and PBP1/ATXN2 may serve as one of the mechanisms of PBP1/ATXN2-mediated toxicity. These results extend the spectrum of ALS associated proteins whose toxicity is regulated by PBP1/ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.
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Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies
PLoS genetics, 2019Co-Authors: Sangeun Park, Seikyoung Park, Naruaki Watanabe, Tadafumi Hashimoto, Takeshi Iwatsubo, Tatyana A. Shelkovnikova, Susan W LiebmanAbstract:Proteins associated with familial neurodegenerative disease often aggregate in patients’ neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1, reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral sclerosis (ALS) risk factor and therapeutic target. Likewise, new yeast neurodegenerative disease models could facilitate identification of other risk factors and targets. Mutations in SS18L1, encoding the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS. We show that CREST is toxic in yeast and forms nuclear and occasionally cytoplasmic foci that stain with Thioflavin-T, a dye indicative of amyloid-like protein. Like the yeast chromatin-remodeling factor SWI1, CREST inhibits silencing of FLO genes. Toxicity of CREST is enhanced by the [PIN+] prion and reduced by deletion of the HSP104 chaperone required for the propagation of many yeast prions. Likewise, deletion of PBP1 reduced CREST toxicity and aggregation. In accord with the yeast data, we show that the Drosophila ortholog of human ATXN2, dAtx2, is a potent enhancer of CREST toxicity. Downregulation of dAtx2 in flies overexpressing CREST in retinal ganglion cells was sufficient to largely rescue the severe degenerative phenotype induced by human CREST. Overexpression caused considerable co-localization of CREST and PBP1/ATXN2 in cytoplasmic foci in both yeast and mammalian cells. Thus, co-aggregation of CREST and PBP1/ATXN2 may serve as one of the mechanisms of PBP1/ATXN2-mediated toxicity. These results extend the spectrum of ALS associated proteins whose toxicity is regulated by PBP1/ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.
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calcium responsive transactivator crest toxicity is rescued by loss of pbp1 ATXN2 function in a novel yeast proteinopathy model and in transgenic flies
bioRxiv, 2019Co-Authors: Sangeun Park, Seikyoung Park, Naruaki Watanabe, Tadafumi Hashimoto, Takeshi Iwatsubo, Tatyana A. Shelkovnikova, Susan W LiebmanAbstract:Proteins associated with familial neurodegenerative disease often aggregate in patients9 neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1, reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral sclerosis (ALS) risk factor and therapeutic target. Likewise, new yeast neurodegenerative disease models could facilitate identification of other risk factors and targets. Mutations in SS18L1, encoding the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS. We show that CREST is toxic in yeast and, like the yeast chromatin-remodeling factor SWI1, CREST inhibits silencing of FLO genes. Toxicity of CREST is enhanced by the [PIN+] prion and reduced by deletion of PBP1/ATXN2. CREST forms nuclear and occasionally cytoplasmic foci that stain with an amyloid dye. Overexpression of PBP1 caused considerable CREST co-localization with PBP1 tagged cytoplasmic granules which might promote toxic aggregation of CREST. In accord with the yeast data, we show that the Drosophila ortholog of human ATXN2, dAtx2, is a potent enhancer of CREST toxicity. Down regulation of dAtx2 in flies overexpressing CREST in retinal ganglion cells was sufficient to almost entirely rescue the severe degenerative phenotype induced by human CREST. These results extend the spectrum of ALS associated proteins affected by PBP1/ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.
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a yeast model of calcium responsive transactivator protein crest proteinopathy shows that pbp1 ATXN2 modifies crest aggregation and toxicity
bioRxiv, 2018Co-Authors: Sangeun Park, Seikyoung Park, Susan W LiebmanAbstract:Proteins encoded by genes that cause familial neurodegenerative disease often form insoluble amyloid-like aggregates in diseased patient neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Finding that deletion of the ATXN2 ortholog, PBP1, reduced yeast TDP-43 toxicity, lead to discoveries that ATXN2 is an amyotrophic lateral sclerosis (ALS) risk factor and that lowered ATXN2 levels are therapeutic in a mouse ALS model. Likewise, new yeast neurodegenerative disease models could allow identification of disease risk factors and provide a drug discovery platform. Mutations in SS18L1, which encodes CREST, are associated with ALS. CREST, a chromatin-remodeling factor, contains an aggregation prone domain. Here, we show that CREST is toxic in yeast and inhibits silencing of telomerically located genes. Toxicity is enhanced by the [PIN+] prion and reduced by deletion of PBP1/ATXN2. CREST forms nuclear and occasionally cytoplasmic foci that stain with an amyloid dye. Overexpression of PBP1 caused considerable CREST co-localization with PBP1 tagged cytoplasmic granules which might promote toxic aggregation of CREST. These results extend the spectrum of ALS associated proteins affected by PBP1/ATXN2, supporting the hypothesis that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.
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A yeast model of calcium-responsive transactivator protein (CREST) proteinopathy shows that PBP1/ATXN2 modifies CREST aggregation and toxicity
2018Co-Authors: Sangeun Park, Seikyoung Park, Susan W LiebmanAbstract:Proteins encoded by genes that cause familial neurodegenerative disease often form insoluble amyloid-like aggregates in diseased patient neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Finding that deletion of the ATXN2 ortholog, PBP1, reduced yeast TDP-43 toxicity, lead to discoveries that ATXN2 is an amyotrophic lateral sclerosis (ALS) risk factor and that lowered ATXN2 levels are therapeutic in a mouse ALS model. Likewise, new yeast neurodegenerative disease models could allow identification of disease risk factors and provide a drug discovery platform. Mutations in SS18L1, which encodes CREST, are associated with ALS. CREST, a chromatin-remodeling factor, contains an aggregation prone domain. Here, we show that CREST is toxic in yeast and inhibits silencing of telomerically located genes. Toxicity is enhanced by the [PIN+] prion and reduced by deletion of PBP1/ATXN2. CREST forms nuclear and occasionally cytoplasmic foci that stain with an amyloid dye. Overexpression of PBP1 caused considerable CREST co-localization with PBP1 tagged cytoplasmic granules which might promote toxic aggregation of CREST. These results extend the spectrum of ALS associated proteins affected by PBP1/ATXN2, supporting the hypothesis that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.
Karla P Figueroa - One of the best experts on this subject based on the ideXlab platform.
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ALS-associated genes in SCA2 mouse spinal cord transcriptomes.
Human molecular genetics, 2020Co-Authors: Daniel R. Scoles, Karla P Figueroa, Lance Pflieger, Warunee Dansithong, Sharan Paul, Frank Rigo, Mandi Gandelman, C. Frank Bennett, Stefan M. PulstAbstract:The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Nature Communications, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2. Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration.
Nature communications, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Nature Publishing Group, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2
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ATXN2 antisense therapy improves sca2 mouse motor and purkinje cell electrophysiological phenotypes s17 001
Neurology, 2017Co-Authors: Daniel R. Scoles, Karla P Figueroa, Matthew Schneider, Frank Rigo, Thomas S. Otis, Pratap Meera, Frank Bennett, Stefan M. PulstAbstract:Objective: Testing of antisense oligonucleotide (ASO) therapy for lowering ATXN2 expression and modification of the motor and electrophysiological phenotypes of two SCA2 mouse models. Background: Spinocerebellar ataxia type 2 (SCA2) is caused by CAG repeat expansion in the ATXN2 gene resulting in polyglutamine expanded ATXN2 protein and pathogenic gain of toxic function. Design/Methods: SCA2 mice were treated by intracerebroventricular (ICV) injection of ASOs. Motor phenotypes were determined by rotarod testing, cerebellar molecular phenotypes were determined by qPCR, and PC firing frequencies (FFs) were determined by extracellular recordings in acute cerebellar slices. Results: Both ATXN2-Q127 mice and BAC-ATXN2-Q72 mice exhibit progressive age-dependent rotarod phenotypes. Symptomatic ATXN2-Q127 mice treated ICV with ASO7 at 8 wks of age had a significantly improved rotarod performance at 18 weeks of age vs. saline treated control mice (n=15, P Conclusions: A single treatment of ASO7 lowered ATXN2 expression resulting in restoration of PC FF even well after onset of SCA2 mouse motor phenotype and significantly improved the rotarod phenotype in both mouse models. Study Supported by: Supported by NIH grants R21NS081182, R01NS033123, & R37NS033123. Disclosure: Dr. Scoles has nothing to disclose. Dr. Schneider has nothing to disclose. Dr. Meera has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Rigo has nothing to disclose. Dr. Bennett has received personal compensation for activities with Ionis Pharmaceuticals, Inc. as an employee. Dr. Bennett holds stock and/or stock options in Ionis Pharmaceuticals Inc. Dr. Otis has nothing to disclose. Dr. Pulst has received personal compensation in an editorial capacity for the American Academy of Neurology, Neurology: Genetics. Dr. Pulst has received royalty payments from Cedars-Sinai Medical Center.
Sharan Paul - One of the best experts on this subject based on the ideXlab platform.
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ALS-associated genes in SCA2 mouse spinal cord transcriptomes.
Human molecular genetics, 2020Co-Authors: Daniel R. Scoles, Karla P Figueroa, Lance Pflieger, Warunee Dansithong, Sharan Paul, Frank Rigo, Mandi Gandelman, C. Frank Bennett, Stefan M. PulstAbstract:The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Nature Communications, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2. Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration.
Nature communications, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
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Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Nature Publishing Group, 2018Co-Authors: Sharan Paul, Karla P Figueroa, Daniel R. Scoles, Warunee Dansithong, Stefan M. PulstAbstract:Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2
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ATXN2-AS, a gene antisense to ATXN2, is associated with spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis.
Annals of neurology, 2016Co-Authors: Xin Sun, Sharan Paul, Guangbin Xia, Nicolas Arbez, Shanshan Zhu, H. Benjamin Peng, Christopher A. Ross, Arnulf H. Koeppen, Russell L. MargolisAbstract:Objective Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the gene ataxin-2 (ATXN2). ATXN2 intermediate-length CAG expansions were identified as a risk factor for amyotrophic lateral sclerosis (ALS). The ATXN2 CAG repeat is translated into polyglutamine, and SCA2 pathogenesis has been thought to derive from ATXN2 protein containing an expanded polyglutamine tract. However, recent evidence of bidirectional transcription at multiple CAG/CTG disease loci has led us to test whether additional mechanisms of pathogenesis may contribute to SCA2. Methods In this work, using human postmortem tissue, various cell models, and animal models, we provide the first evidence that an antisense transcript at the SCA2 locus contributes to SCA2 pathogenesis. Results We demonstrate the expression of a transcript, containing the repeat as a CUG tract, derived from a gene (ATXN2-AS) directly antisense to ATXN2. ATXN2-AS transcripts with normal and expanded CUG repeats are expressed in human postmortem SCA2 brains, human SCA2 fibroblasts, induced SCA2 pluripotent stem cells, SCA2 neural stem cells, and lymphoblastoid lines containing an expanded ATXN2 allele associated with ALS. ATXN2-AS transcripts with a CUG repeat expansion are toxic in an SCA2 cell model and form RNA foci in SCA2 cerebellar Purkinje cells. Finally, we detected missplicing of amyloid beta precursor protein and N-methyl-D-aspartate receptor 1 in SCA2 brains, consistent with findings in other diseases characterized by RNA-mediated pathogenesis. Interpretation These results suggest that ATXN2-AS has a role in SCA2 and possibly ALS pathogenesis, and may therefore provide a novel therapeutic target for these diseases. Ann Neurol 2016;80:600–615
