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Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2

ABSTRACT: ATXN2 has emerged as an exciting therapeutic target for neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2), as lowering its levels via genomic knockout or anti-sense oligonucleotide (ASO) treatment has been shown to mitigate disease phenotypes and led to a current clinical trial of ATXN2 ASOs for treatment of ALS in humans. To identify additional ways to lower ataxin‑2 protein levels, we performed a genome-wide fluorescence activated cell sorting (FACS)-based CRISPR screen in human cells and identified multiple components of the lysosomal vacuolar ATPase (v‑ATPase) as modifiers of ataxin‑2 levels. This dataset contains the RNA-sequencing data and CRISPR screen data used to support the conclusions from this study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189417 | GEO | 2022/10/18

REPOSITORIES: GEO

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Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2

Project description:Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). To identify additional ways of reducing ataxin-2 levels, we performed a genome-wide screen in human cells for regulators of ataxin-2 and identified RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a top hit. This dataset contains the RNA-sequencing data used to support the conclusions from this study.

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Ataxin-2 adapts ribosomal mRNA levels and S6 phosphorylation to nutrient availability, with effects on protein synthesis and growth

Project description:Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder, which is caused by an unstable CAG-repeat expansion in the SCA2 gene, that encodes a polyglutamine tract (polyQ-tract) expansion in ataxin-2 protein (ATXN2). The RNA-binding protein ATXN2 interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum or to polysomes. Under cell stress ATXN2 and PABPC1 show redistribution to stress granules where mRNAs are kept away from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates their processing. Here, we investigated Atxn2 knock-out (Atxn2-/-) mouse liver, cerebellum and midbrain regarding their RNA profile, employing oligonucleotide microarrays for screening and RNA deep sequencing for validation. Modest ~1.4-fold upregulations were observed for the level of many mRNAs encoding ribosomal proteins and other translation pathway factors. Quantitative reverse transcriptase PCR and immunoblots in liver tissue confirmed these effects and demonstrated an inverse correlation also with PABPC1 mRNA and protein. ATXN2 deficiency also enhanced phosphorylation of the ribosomal protein S6, while impairing the global protein synthesis rate, suggesting a block between the enhanced translation drive and the impaired execution. Furthermore, ATXN2 overexpression and deficiency retarded cell cycle progression. ATXN2 mRNA levels showed a delayed phasic twofold increase under amino acid and serum starvation, similar to ATXN3, but different from motor neuron disease genes MAPT and SQSTM1. ATXN2 mRNA levels depended particularly on mTOR signalling. Altogether the data implicate ATXN2 in the adaptation of mRNA translation and cell growth to nutrient availability and stress. Factorial design comparing ataxin-2 knock-out mice with wild type littermates in three different tissues (midbrain, cerebellum, liver) and 3 different ages.

2014-10-31 | E-GEOD-55177 | biostudies-arrayexpress

Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation

Project description:Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) functions in translational regulation, mRNA stability, and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which mediates translational activation of some target mRNAs, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA-Binding Proteins Identified by Editing (TRIBE) experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA content of Ataxin-2 mRNP granules. Co-localization and co-immunoprecipitation analyses show that structured interactions between Ataxin-2 and PABP additionally help determine protein components of Ataxin-2-associated mRNP granules and contribute to Ataxin-2’s association with stress granules. Finally, in vivo experiments in Drosophila indicate that while the Atx2-LSm domain protects against neurodegeneration, structured PAM2- and unstructured IDR- interactions both promote degeneration. Taken together the data: (a) lead to a proposal for how Ataxin-2 interactions are remodelled during different stages of translational control; (b) show how structured and non-structured interactions of Ataxin-2 contribute differently to the specificity and efficiency of RNP granule condensation; and (c) demonstrate that the Ataxin-2 protein contains multiple activities that may respectively prevent or promote neurodegeneration.

2024-04-22 | GSE196739 | GEO

Ataxin-2 adapts ribosomal mRNA levels and S6 phosphorylation to nutrient availability, with effects on protein synthesis and growth

2014-10-31 | GSE55177 | GEO

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2017-05-27 | GSE57998 | GEO

Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2

Project description:Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2

| PRJNA782983 | ENA

Transcriptomic analysis of the spinal cords of knock-in adult mice carrying the ATXN2/TDP-43 human transgenes

Project description:Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are a strong genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. To investigate gene expression changes and deregulated pathways caused by ataxin-2 intermediate repeat expansions in presence/absence of mutant TDP-43, we performed RNA sequencing of whole spinal cords from knock-in mice harboring ATXN2 and TDP-43 human transgenes as well as non-transgenic mice (NTg)

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Transcriptomic analysis of iPSC-derived motor neurons from ALS patients carrying ATXN2 intermediate repeat expansions and healthy controls

Project description:Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are a strong genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we developed a human iPSC-derived model to investigate whether motor neurons derived from ALS patients carrying ATXN2 intermediate repeat expansions are transcriptomically distinct from healthy controls. For that, we performed RNA sequencing of motor neurons derived from 5 ATXN2-ALS iPSC lines and 5 healthy controls (HC).

2024-07-16 | GSE224578 | GEO

Transcriptomic analysis of spinal cord microglial cells from NTg and ATXN2-Q33;TDP-43 adult mice

Project description:Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are a strong genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Our study shows that microglial cells might contribute to ALS-related pathology observed in mice carrying ATXN2 intermediate repeat expansions (Q33) in an ALS background (TDP-43). To investigate whether ATXN2-Q33;TDP-43 spinal cord microglia are transcriptomically different from non transgenic counterparts, we performed RNA sequencing of sorted microglial cells from knock-in (ATXN2-Q33;TDP-43) as well as non-transgenic (NTg) mice.

2024-07-16 | GSE224581 | GEO

ATXN2L interacts mainly with NUFIP2, ATXN2L-absence causes NUFIP2 depletion, and ATXN2-polyQ expansion triggers NUFIP2 accumulation (proteome profiles)

Project description:The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. Ataxin-2-like (ATXN2L) is preferentially nuclear, more abundant, essential for embryonic life, and its sequestration into ATXN2 aggregates might contribute to disease. Here, two approaches elucidated ATXN2L roles. We identified (i) interactors by coimmunoprecipitation in wildtype and ATXN2L-null murine embryonic fibroblasts, (ii) proteome profile effects by mass spectrometry in these cells, (iii) ATXN2L interactor accumulation in the SCA2 mouse model Atxn2-CAG100-KnockIn (KIN). We observed RNA-binding proteins PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL to show mostly stronger association with ATXN2L than established interactors (ATXN2, PABPC1, LSM12, and G3BP2). ATXN2L also interacted with actin complex components SYNE2, LMOD1, ACTA2, FYB and GOLGA3. Oxidative stress increased HNRNPK but decreased SYNE2 association, likely reflecting SG relocalization. Among these interactors, proteome profiling revealed NUFIP2 and SYNE2 as depleted in ATXN2L-null fibroblasts. NUFIP2 homodimers and SYNE1 accumulated during the ATXN2 aggregation process in KIN 14-month-old spinal cords. Overall, the functions of ATXN2L and its interactors are important in RNA granule trafficking and surveillance, particularly for differentiated neuron maintenance.

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