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

ABSTRACT: 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)

ORGANISM(S): Mus musculus

PROVIDER: GSE224580 | GEO | 2024/07/16

REPOSITORIES: GEO

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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.

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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).

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

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Transcriptomic characterization of in vitro human iPSC-derived motor neuron systems for the exploration of cell autonomous mechanisms and modifiers of TDP-43 perturbation associated neurotoxicity

Project description:Transactive Response DNA-binding protein 43 (TDP-43) is a multifunctional nuclear protein ubiquitously expressed in all tissues. Although it is primarily nuclear, Amyotrophic Lateral Sclerosis (ALS) patients frequently present with cytoplasmic aggregates of TDP-43 in motor neurons on post-mortem examination. Although only about 5% of all ALS patients have a TARDBP mutation (Ghasemi and Brown 2018; Ingre et al. 2015), which is known to cause these insoluble cytoplasmic aggregates, 97% of ALS patients will develop cytoplasmic, insoluble TDP-43 aggregates regardless of whether they have a mutation in TARDBP or not (Ling et al. 2013). Overexpression of wild-type TDP-43 has previously been shown to be a valid model of inducing neurotoxicity as well as a limited amount of cytoplasmic re-localization and aggregation characteristic of ALS (Elden et al. 2010; Wils et al. 2010). In the search for modifiers of toxicity as conferred by TDP-43 overexpression in these models, knockout of Ataxin-2 (ATXN2) was proposed as a protective intervention in the context of TDP-43 perturbation in non-human model systems (Elden et al. 2010, Becker et al. 2017). This promising finding had not previously been validated in a human motor neuron system, nor had a thorough investigation been conducted to determine the mechanism of neuroprotection that ATXN2 knockout employs to drive the therapeutic effect. This sequencing study examines both ATXN2 intact and ATXN2 knockout motor neurons in the context of TDP-43 perturbation to explore global transcriptomic changes that arise from these changes in cellular state that are associated with progression of ALS (ATXN2 intact) and what pathways could be implicated in protection from ALS-associated neurodegeneration (ATXN2 Knockout).

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Atxn2-Knock-Out mice show branched chain amino acids and fatty acids pathway alterations

Project description:Human Ataxin-2 (ATXN2) gene locus variants have been associated with obesity, diabetes mellitus type 1 and hypertension in genome-wide association studies, while mouse studies showed the knock-out of Atxn2 to lead to obesity, insulin resistance and dyslipidemia. Intriguingly, the deficiency of ATXN2 protein orthologues in yeast and flies rescues the neurodegeneration process triggered by TDP-43 and Ataxin-1 toxicity. To understand the molecular effects of ATXN2 deficiency by unbiased approaches, we quantified the global proteome and metabolome of Atxn2-knock-out mice with label-free mass spectrometry. In liver tissue, significant downregulations of the proteins ACADS, ALDH6A1, ALDH7A1, IVD, MCCC2, PCCA, OTC, together with bioinformatic enrichment of downregulated pathways for branched chain and other amino acid metabolism, fatty acids and citric acid cycle were observed. Statistical trends in the cerebellar proteome and in the metabolomic profiles supported these findings. They are in good agreement with recent claims that PBP1, the yeast orthologue of ATXN2, sequestrates the nutrient sensor TORC1 in periods of cell stress. Overall, ATXN2 appears to modulate nutrition and metabolism, and its activity changes are determinants of growth excess or cell atrophy.

2016-02-08 | PXD003155 | Pride

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

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

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Atxn2-Knock-Out mice show branched chain amino acids and fatty acids pathway alterations

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

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

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Transcriptomic profiling of purified mature olfactory sensory neurons from transgenic mice expressing genomically encoded double-stranded RNA

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2021-03-01 | GSE166307 | GEO

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Project description:The TDP-43 proteinopathies, which include amyotrophic lateral sclerosis and frontotemporal dementia, are a devastating group of neurodegenerative disorders that are characterized by the mislocalization and aggregation of TDP-43. Here we demonstrate that RNA-targeting CRISPR effector proteins, a programmable class of gene silencing agents that includes the Cas13 family of enzymes and Cas7-11, can be used to mitigate TDP-43 pathology when programmed to target ataxin-2, a modifier of TDP-43-associated toxicity. In addition to inhibiting the aggregation and transit of TDP-43 to stress granules, we find that the in vivo delivery of an ataxin-2-targeting Cas13 system to a mouse model of TDP-43 proteinopathy improved functional deficits, extended survival, and reduced the severity of neuropathological hallmarks. Further, we benchmark RNA-targeting CRISPR platforms against ataxin-2 and find that high-fidelity forms of Cas13 possess improved transcriptome-wide specificity compared to Cas7-11 and a first-generation effector. Our results demonstrate the potential of CRISPR technology for TDP-43 proteinopathies.

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