Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE132108 | GEO | 2019/06/04
REPOSITORIES: GEO
Similar Datasets
Project description:Staufen2 (Stau2) is an RNA-binding protein that is involved in dendritic spine morphogenesis and function. Several studies have recently investigated the role of Stau2 in the regulation of its neuronal target mRNAs, with particular focus on the hippocampus. Here, we provide evidence for Stau2 expression and function in cerebellar Purkinje cells. We show that Stau2 downregulation (Stau2GT) lead to an increase of the glutamate receptor ionotropic delta subunit 2 (GluD2) in Purkinje cells when animals performed physical activity by voluntary wheel running. Furthermore, Stau2GT mice showed lower performance in motor coordination assays but enhanced motor learning abilities, concomitantly with an increase in dendritic GluD2 expression. Together, our results suggest a novel role of Stau2 in Purkinje cell synaptogenesis in the mouse cerebellum
2019-04-23 | GSE126996 | GEO
Project description:We show that GFP-(GR)100-expressing mice developed age-dependent neurodegeneration, brain atrophy, as well as motor and memory impairments through the accumulation of diffuse, cytoplasmic poly(GR).
2019-02-04 | GSE112931 | GEO
Project description:Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients with the C9orf72 mutation show predominantly cytoplasmic aggregates of poly-GR and poly-PR proteins that are acutely toxic in various model systems. To identify the molecular mediators of neurotoxicity of poly-GR/PR, we analyzed their interactomes in primary neurons. GFP-(GR)149 and (PR)175-GFP preferentially interacted with RNA-binding proteins, including stress granule-associated and nucleolar proteins, as well as ribosomes. Overexpression of the poly-GR/PR interactors Staufen 1/2 (STAU1/2) and YBX1 led to cytoplasmic aggregation of poly-GR/PR into large stress granule-like inclusions, while the poly-GR/PR interactor nucleophosmin (NPM1) recruited poly-GR into the nucleolus. In addition, poly-PR expression reduced ribosome levels and translation, which is consistent with the widespread reduction of synaptic proteins detected by proteomics. Surprisingly, only GFP-(GR)53, but not GFP-(GR)149, localized to the nucleolus and reduced ribosome levels and translation in neurons, suggesting impaired ribosome biogenesis is driving the acute toxicity commonly observed in vitro. In C9orf72 patient brains, we detected co-aggregation of poly-GR/PR inclusions with ribosomes, but not stress granules. Partial sequestration of ribosomes may chronically impair protein synthesis and contribute to C9orf72 ALS/FTD pathogenesis.
2018-06-27 | PXD008691 | Pride
Project description:Cellular diversification is a fundamental feature of the brain that is critical for physiological functions of the nervous system including perception, motor control, and learning and memory. Advances in single cell RNA-sequencing have led to characterization of transcriptomic profiles of distinct major types of neurons in the brain. However, how transcriptomic profiles diversify within a specific population of neurons and their links to function remain poorly understood. Purkinje neurons represent some of the most iconic cells in the brain with decades of research characterizing their anatomy, cell biology, physiology, and roles in plasticity, learning and memory, as well as in diseases of the nervous system. In this study, we deployed an approach of isolating nuclei tagged in specific cell types followed by cell sorting and single nuclear RNA sequencing to profile Purkinje neurons and their response to motor activity and learning in adult mice. We uncovered the molecular map of two major subpopulations of Purkinje neurons, identified by the hallmark genes Aldoc and Plcb4, which bear distinct transcriptomic features. Remarkably, Plcb4+, but not Aldoc+, Purkinje neurons display robust plasticity of gene expression in mice subjected to sensorimotor and learning experience with downregulation of gene clusters related to chromatin regulation and synaptic organization and upregulation of gene clusters related to neuronal activity and synaptic transmission and neuron-immune interactions. Using in vivo calcium imaging and optogenetics perturbation approaches, we show that activation of Plcb4+ Purkinje neuron plays a crucial role in associative motor learning. Upon integrating single nuclear RNA-seq datasets with weighted gene network analysis, we also identify a motor activity and learning specific gene module that includes components of the FGFR2-SOS1-MAPK signaling pathway in Plcb4+ Purkinje neurons. Knockout of FGFR2 in Plcb4+ Purkinje neurons in adult mice by a CRISPR approach dramatically disrupts motor learning. Our findings provide a platform for identification of subpopulations of neurons and define how diversification of Purkinje neurons in the cerebellum links to their responses to motor learning. Our study, and by extension similar studies in the human brain, will provide the foundation for understanding the selective vulnerability of Plcb4+ Purkinje neurons to neurological diseases.
2022-05-11 | GSE153184 | GEO
Project description:How G4C2 repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. Here, we report the first mouse model to express poly(PR), a dipeptide repeat protein synthesized from expanded G4C2 repeats. Expression of GFP-(PR)50 throughout the mouse brain yielded progressive brain atrophy, neuron5 loss, loss of poly(PR)-positive cells and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused abnormal histone methylation, lamin invaginations, decreases in HP1α expression, and disruptions of HP1α liquid phases. These aberrations of histone methylation, lamins and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element10 expression and double-stranded RNA accumulation. Thus, we uncover new mechanisms by which poly(PR) contributes to c9FTD/ALS pathogenesis.
2019-05-29 | GSE124834 | GEO
Project description:Mice heterozygous for a null mutation in Widely-interspaced zinc finger, Wiz, were produced in a screen for modifiers of epigenetic reprogramming; expression of the GFP reporter transgene decreased in mutants, suggesting a role in transcriptional activation (Daxinger et al., 2013). These mice are viable and fertile, with no overt abnormalities and homozygosity for the mutation is embryonic lethal (Daxinger et al, 2013). Wiz is expressed at high levels in the brain, both in the embryo and in the adult, but there have been no reports of its role in neural tissue. To address this, ChIP-seq, using an anti-Wiz antibody, was carried out in adult cerebellum. Wiz peaks were found at tens of thousands of sites across the genome, many of which are gene promoters that show enrichment for the pioneer transcription factor CTCF. RNA-seq, using WizMommeD30/+ and Wiz+/+ mice, revealed that some genes were affected by haploinsufficiency of Wiz; ~30 in the brains of mid-gestation embryos and ~80 in adult cerebellum. Most genes that were deregulated in embryonic brain of heterozygous mutants decreased in expression and include a group of clustered protocadherin genes that were also down-regulated in adult cerebellum. The enhancer of this gene cluster has a strong Wiz peak in the ChIP-seq data and has been reported, by others, to be activated by CTCF in neurons.
2016-07-14 | GSE76909 | GEO
Project description:Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with an amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes with expression corrected to WT levels in Atxn1175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum.
2022-12-01 | GSE218303 | GEO
Project description:Loss of Tmem106b leads to cerebellum Purkinje cell death and motor deficits
| PRJNA693266 | ENA
Project description:Contactin-associated protein-like 2 (Caspr2) is a neurexin-like protein that has been associated with numerous neurological conditions. However, the mechanisms underlying Caspr2 function in the central nervous system remain incompletely understood. Here, we report on a functional role for Caspr2 in the developing cerebellum. Loss of Caspr2 impairs Purkinje cell dendritic development, alters cell signaling and results in motor coordination deficits. Caspr2 is highly enriched at synaptic specializations in the cerebellum. Using a proteomic approach, we identify type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) as a specific synaptic interaction partner of the Caspr2 extracellular domain (ECD) in the molecular layer (ML) of the developing cerebellum. The interaction of Caspr2 ECD with IP3R1 inhibits IP3R1-mediated changes in cellular morphology. Together, our work defines a mechanism by which Caspr2 controls the development and function of the cerebellum, and advances our understanding of how Caspr2 dysfunction might lead to specific brain disorders.
2020-07-13 | PXD018972 | Pride
Project description:Aim of the study was to examine the expression of calsequestrin isoforms in zebrafish adult brain. By quantitative PCR we found three RNA transcripts coding for Casq1a, Casq1b and Casq2. In brain homogenate, two protein isoforms were detected by western blotting and mass spectrometry. Whole brain fractionation experiments revealed that Casq2 isoform was enriched in a heavy fraction containing microsomes and synaptic membranes, while Casq1a was recovered also in a light cytosolic-enriched fraction. By immunofluorescence, we found that calsequestrins show different cellular localization and we confirmed heterogeneous cell expression of Casq1a and Casq2 mRNA by in situ hybridization. Both isoforms were expressed in cerebellum, and cerebellum-like structures of the brain, Casq2 more concentrated in Purkinje cells, and Casq1 equally distributed in granular and Purkinje cells. At sub cellular level, in Purkinje cells, Casq2 was localized in cell bodies, dendrites and axons, while Casq1 was restricted to cell bodies and axons. Data are discussed in relation to the heterogeneous cellular and subcellular distribution of other Calcium store markers of cerebellum and are evaluated with respect to the relevance of calsequestrins in neuron-specific functional activity.
2020-05-27 | PXD015577 | Pride