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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE108256 | 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 2)

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

2018-04-24 | GSE108255 | GEO

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

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

Project description:Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain- and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity.

| S-EPMC6422678 | biostudies-literature

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

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

Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1.

Project description:Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative disease in that it is caused by a mutation in a broadly expressed protein, ATXN1; however, only select populations of cells degenerate. The interaction of polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis; however, the importance of this interaction in other vulnerable cells remains unknown. Here, we mutated the 154Q knockin allele of Atxn1154Q/2Q mice to prevent the ATXN1-CIC interaction globally. This normalized genome-wide CIC binding; however, it only partially corrected transcriptional and behavioral phenotypes, suggesting the involvement of additional factors in disease pathogenesis. Using unbiased proteomics, we identified three ATXN1-interacting transcription factors: RFX1, ZBTB5, and ZKSCAN1. We observed altered expression of RFX1 and ZKSCAN1 target genes in SCA1 mice and patient-derived iNeurons, highlighting their potential contributions to disease. Together, these data underscore the complexity of mechanisms driving cellular vulnerability in SCA1.

| S-EPMC9957872 | biostudies-literature

Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1

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

2022-12-13 | GSE218302 | GEO

Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1 [CUT&RUN]

Project description:Genome wide binding profiles of CIC and H3K27ac in CIC KO (Engrailed1-Cre;Cicfl/fl), wildtype, Atxn1_154Q/2Q (SCA1), and Atxn1_154Q[V5591A;S602D]/2Q (154Q AXH) in the cerebellum

2022-12-13 | GSE218301 | GEO

Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1 [RNA-seq]

Project description:mRNA profiles of 10-week mice in wild-type (WT), Atxn1_154Q/2Q (SCA1), Atxn1_154Q[V5591A;S602D]/2Q (154Q AXH) genotypes across 5 different brain regions (cerebellum, brainstem, hippocampus, striatum and cortex)

2022-12-13 | GSE218283 | GEO

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