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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)

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

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

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