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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE218301 | GEO | 2022/12/13

REPOSITORIES: GEO

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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

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.

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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

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

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

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

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

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

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Therapeutic effects of ASO-mediated reduction of Atxn1 in a SCA1 Mouse Mode: Proof of concept with distinct disease-associated transcriptome profiles in cerebellum and medulla

Project description:RNA-targeting approaches have improved disease symptoms in preclinical rodent models of several neurological diseases. Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited ataxia caused by expansion of a polyglutamine tract in the encoded protein Ataxin-1 (ATXN1). Despite advances in understanding this CAG repeat/polyglutamine expansion disease, there are still no therapies to alter its progressive fatal course. Here we investigate the therapeutic capability of an antisense oligonucleotide (ASO) targeting mouse Atxn1 in Atxn 1 154Q/2Q knockin mice that manifest motor deficits and premature lethality. Following a single ASO treatment at 5 weeks of age, mice demonstrated rescue of these disease-associated phenotypes. In addition, RNA-seq on vehicle-treated Atxn1 154Q/2Q and ASO-treated Atxn1 154Q/2Q mice were used to demonstrate molecular differences between SCA1 pathogenesis in the cerebellum that underlies ataxia with disease in the medulla associated with lethality. Together, these findings support the efficacy and therapeutic importance of directly targeting ATXN1 expression as a strategy to rescue both motor deficits and lethality seen in SCA1.

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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.

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Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1

Project description:Purpose: The goals of this study were to identify the molecular alterations in the SCA1 inferior olive, and determine whether these changes are found in other affected tissues. Methods: mRNA profiling was conducted in two different SCA1 mouse models (Atxn1 154Q/2Q KI and ATXN1-82Q Tg), in two different affected tisues (inferior olive and cerebellum) during early disease initiation and progression (5 week and 12 week time-points). All analyses were conducted relative to appropriate wild-type controls. TopHat2 v2.1.0 was utilized to align reads to the mouse reference genome (mm10) before quantification and differential expression analysis with Cufflinks v2.2.1. Normalized expression values were generated using Cuffnorm. Results: Differentially regulated genes identified in the SCA1 inferior olive segregated into several enriched biological pathways, including the Defense Response at 12 weeks of age. Our study demonstrates that vulnerable tissues in SCA1 are not uniform in their gene expression changes, and express discrete and commonly enriched biological pathways. In addition, we found that brain region-specific differences occur early in disease initiation and progression at 5 weeks of age. Conclusions: The findings from this study suggest that different mechanisms of neurodegeneration are at work in the SCA1 inferior olive and cerebellum.

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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.

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