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Gain of function of the ATXN1-CIC complex drives cerebellar pathology in Spinocerebellar ataxia type 1 (part 2)

ABSTRACT: We isolated RNA from cerebella dissected from Pcp2-ATXN1[82Q], Pcp2-ATXN1[82Q]V591A;S602D, and wild-type littermates at one year of age

ORGANISM(S): Mus musculus

PROVIDER: GSE108255 | GEO | 2018/04/24

REPOSITORIES: GEO

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Gain of function of the ATXN1-CIC complex drives cerebellar pathology in Spinocerebellar ataxia type 1 (part 1)

Project description:We isolated RNA from cerebella dissected from En1-Cre; Cicflox/flox and Cicflox/+ littermates at one year of age

2018-04-24 | GSE108254 | GEO

Cholecystokinin 1 Receptor (Cck1R) Activation Restores Normal mTORC1 signaling and is Protective to Purkinje cells of SCA Mice

Project description:Spinocerebellar Ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often in cerebellar Purkinje neurons. A SCA1 mouse model, Pcp2-ATXN1[30Q]D776, has severe ataxia in absence of progressive Purkinje neuron degeneration and death. Previous RNA-seq analyses identified cerebellar up-regulation of the peptide hormone Cholecystokinin (Cck) in Pcp2-ATXN1[30Q]D776 mice. Importantly, absence of Cck1 receptor (Cck1R) in Pcp2-ATXN1[30Q]D776 mice confers a progressive disease with Purkinje neuron death. A Cck1R agonist, A71623 administered to Pcp2-ATXN1[30Q]D776;Cck-/- and Pcp2-AXTN1[82Q] mice dampened Purkinje neuron pathology and associated deficits in motor performance. In addition, A71623 administration improved motor performance of Pcp2-ATXN2[127Q] SCA2 mice. Moreover, the Cck1R agonist A71623 corrected mTORC1 signaling and improved expression of calbindin in cerebella of AXTN1[82Q] and ATXN2[127Q] mice. These results indicate that manipulation of the Cck-Cck1R pathway is a potential therapeutic target for treatment of diseases involving Purkinje neuron degeneration.

2022-01-11 | GSE180969 | GEO

Reduction of Protein Kinase A-mediated Phosphorylation of ATXN1-S776 in Purkinje Cells Delays Onset of Ataxia in a SCA1 Mouse Model.

Project description:Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation. We further examine the implications of PKA-mediated phosphorylation at ATXN1-S776 on SCA1 through genetic manipulation of the PKA catalytic subunit Cα in Pcp2-ATXN1[82Q] mice. Here we show that pharmacologic inhibition of S776 phosphorylation in transfected cells and SCA1 patient iPSC-derived neuronal cells lead to a decrease in ATXN1. In vivo, reduction of PKA-mediated ATXN1-pS776 results in enhanced degradation of ATXN1 and improved cerebellar-dependent motor performance. These results provide evidence that PKA is a biologically important kinase for ATXN1-pS776 in cerebellar Purkinje cells.

2019-05-31 | GSE114815 | GEO

ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism.

Project description: Not available

| S-EPMC6422678 | biostudies-literature

Gain of function of the ATXN1-CIC complex drives cerebellar pathology in Spinocerebellar ataxia type 1

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-04-24 | GSE108256 | GEO

Gain of function of the ATXN1-CIC complex drives cerebellar pathology in Spinocerebellar ataxia type 1

Project description:Gain of function of the ATXN1-CIC complex drives cerebellar pathology in Spinocerebellar ataxia type 1

| PRJNA422984 | ENA

Transcriptomic approach reveals splicing dysregulation in spinocerebellar ataxia type 1

Project description:Spinocerebellar ataxia type 1 (SCA1) is caused by a polyglutamine expansion in the ATXN1 gene leading to an expanded polyglutamine tract in the ATAXIN-1 protein. Ataxin-1 is broadly expressed throughout the brain and is known to be involved in regulating gene expression; however, it is not yet determined if mutant ataxin-1 regulates alternative splicing events. Utilizing SCA1 mouse models, we performed bulk RNA sequencing and looked for misregulated alternative splicing (mAS) events in SCA1 mouse cerebella. We found that mutant ataxin-1 causes mAS events to occur in the SCA1 mouse cerebella. Furthermore, we showed that abnormal splicing events predominantly occur in cell types that express mutant ataxin-1. Less than 25% of the mAS events were also differentially expressed genes (DEGs) and therefore their transcriptional dysregulation was previously unknown in the context of SCA1. We show through gene ontology analysis that mAS events reveal new biological pathways: mAS events showed changes in structural morphogenesis whereas DEGs showed changes in ion channel and transmembrane transport. We also report that mutant ataxin-1 causes dysregulation of expression of other ataxia-causing genes, providing evidence for molecular basis of clinical similarity among otherwise heterogeneous inherited cerebellar ataxias. We also identified the potential mechanism by which mutant ATXN1 causes mAS through its interaction with RBFOX1.

2023-10-20 | GSE232368 | GEO

Gain of function of the ATXN1-CIC complex drives cerebellar pathology in Spinocerebellar ataxia type 1 (part 2)

Project description:Gain of function of the ATXN1-CIC complex drives cerebellar pathology in Spinocerebellar ataxia type 1 (part 2)

| PRJNA422988 | ENA

Gain of function of the ATXN1-CIC complex drives cerebellar pathology in Spinocerebellar ataxia type 1 (part 1)

Project description:Gain of function of the ATXN1-CIC complex drives cerebellar pathology in Spinocerebellar ataxia type 1 (part 1)

| PRJNA422989 | ENA

RNA-seq of Spinocerebellar Ataxia Type2 (SCA2) transgenic mouse lines and age-matched wild-type

Project description:Spinocerebellar ataxia type 2 (SCA2) is among the progressive neurodegenerative polyglutamine (polyQ) diseases. It is caused by a CAG repeat expansion in an encoded region of the ATXN2 gene giving rise to an expanded polyQ domain in the encoded ATXN2 protein. SCA2 is an autosomal dominant disorder characterized by symptoms resulting from neurodegeneration of cerebellar Purkinje cells. To molecularly characterize SCA2 disease progression, we analyzed RNA-sequencing data produced using the cerebella of ATXN2Q127 mice collected at three distinct time points. The ATXN2Q127 mouse model contains 127 CAG repeats in the full-length ATXN2 cDNA under the control of the PC targeted Pcp2 promoter.

2017-12-09 | E-MTAB-6293 | biostudies-arrayexpress

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