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ATAXIN-2 Intermediate-length Polyglutamine Expansions Elicit ALS-associated Metabolic and Immune Phenotypes

ABSTRACT: ATAXIN-2 Intermediate-length Polyglutamine Expansions Elicit ALS-associated Metabolic and Immune Phenotypes

PROVIDER: PRJNA931912 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23347126_1.fastq.gz	Fastqsanger.gz
	SRR23347126_2.fastq.gz	Fastqsanger.gz
	SRR23347127_1.fastq.gz	Fastqsanger.gz
	SRR23347127_2.fastq.gz	Fastqsanger.gz
	SRR23347128_1.fastq.gz	Fastqsanger.gz

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ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes.

Project description:Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest 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 combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43Tg-ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy.

| S-EPMC11362472 | biostudies-literature

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

ATAXIN-2 Intermediate-length Polyglutamine Expansions Elicit ALS-associated Metabolic and Immune Phenotypes

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

2024-07-16 | GSE224585 | GEO

Single-cell RNA sequencing analysis of iPSC-derived motor neurons from an ALS patient carrying ATXN2 intermediate repeat expansions and a healthy control

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 an ALS patient carrying ATXN2 intermediate repeat expansions (ALS-G) are transcriptomically distinct from a healthy control(OH2.6). For that, we generated a single cell RNA sequencing dataset consisting of a total of 384 cells.

2024-07-16 | GSE224582 | GEO

Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.

Project description:The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.

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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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Epigenetic Dysregulation by Polyglutamine-expanded Ataxin-7 In The mouse model of SCA7

Project description:Epigenetic Dysregulation by Polyglutamine-expanded Ataxin-7 In The mouse model of SCA7

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PolyQ-expanded ataxin-1 formed insoluble protein inclusions perturbing translation in a spinocerebellar ataxia type-1 model

Project description:Spinocerebellar ataxia type-1 is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1 protein. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are linked to neuronal death. Here, we describe a nuclear protein aggregation model of pathogenic human ataxin-1. Using an inducible Sleeping Beauty transposon system, we overexpressed ATXN1Q82 gene in human mesenchymal stem cells that are resistant to the early cytotoxic effects of the mutant protein. We characterized the structure and the protein composition of insoluble polyQ IIBs which gradually occupy the nuclei. In response to their formation, our transcriptome analysis reveals a cerebellum-specific perturbed protein interaction network, primarily affecting protein translation. Our study resolves the previously unknown architecture of insoluble polyQ IIBs and suggests that they affect the assembly and the function of the ribosome. Our inducible cell system faithfully models a human cerebellum at the end-stage of the disease.

2020-02-18 | PXD012709 | Pride

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

Analysis of the expression of Ataxin-2-target genes

Project description:We recently identified the RNA targets of Ataxin-2 by using PAR-CLIP. To elucidate the functional role of Ataxin-2 on target-binding, we have knocked down or overexpressed Ataxin-2 in HEK293T cells and extracted RNAs 48 hrs after transfection. Then, these total RNAs were subjected to whole transcripts microarray analysis to examine how the perturbation of Ataxin-2 expression affects target gene expression. Ataxin-2 was either knocked down using siRNA or overexpressed using the expression construct of Halo-Ataxin-2.Control siRNA was transfected as a control of knockdown experiment. The expression construct of Halo-tag alone was used as a control of overexpression experiment. Forty-eight hrs after transfection, total RNAs were extracted and subjected to microarray analysis.

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