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Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease

ABSTRACT: Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease

PROVIDER: PRJNA663594 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12644300.fastq.gz	Fastqsanger.gz
	SRR12644301.fastq.gz	Fastqsanger.gz
	SRR12644302.fastq.gz	Fastqsanger.gz
	SRR12644303.fastq.gz	Fastqsanger.gz
	SRR12644304.fastq.gz	Fastqsanger.gz

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Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease [microglia]

Project description:Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease [microglia]

| PRJNA663596 | ENA

Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease [microglia]

Project description:Gaucher disease (GD) is currently the focus of considerable attention due primarily to the association between the gene that causes GD (GBA) and Parkinson’s disease. Mouse models exist for the systemic (type 1) and for the acute neuronopathic forms (type 2) of GD. Here we report the generation of a mouse that phenotypically models chronic neuronopathic type 3 GD. Gba-/-;Gbatg mice, which contain a Gba transgene regulated by doxycycline, accumulate moderate levels of the offending substrate in GD, glucosylceramide, and live for up to 10 months, i.e. significantly longer than mice which model type 2 GD. Gba-/-;Gbatg mice display behavioral abnormalities at ~4 months, which deteriorate with age, along with significant neuropathology including loss of Purkinje neurons. Gene expression is altered in the brain and in isolated microglia, although the changes in gene expression are less extensive than in mice modeling type 2 disease. Finally, bone deformities are consistent with the Gba-/-;Gbatg mice being a genuine type 3 GD model. Together, the Gba-/-;Gbatg mice share pathological pathways with acute neuronopathic GD mice but also display differences that might help understand the distinct disease course and progression of type 2 and 3 patients.

2020-11-08 | GSE157991 | GEO

Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease [whole brain]

2020-11-08 | GSE157987 | GEO

Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease [whole brain]

Project description:Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease [whole brain]

| PRJNA663593 | ENA

Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease

Project description:Gaucher disease (GD) results from mutations in the GBA1 gene, which encodes lysosomal glucocerebrosidase (GCase). The large number of mutations known to date in the gene lead to a heterogeneous disorder, which is divided into a non-neuronopathic, type 1 GD, and two neurological, type 2 and type 3, forms. We studied the two fly GBA1 orthologs, GBA1a and GBA1b. Each contains a Minos element insertion, which truncates its coding sequence. In the GBA1am/m flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. However, GBA1bm/m mutant flies presented a significant decrease in GCase activity with concomitant substrate accumulation, which included C14:1 glucosylceramide and C14:0 glucosylsphingosine. GBA1bm/m mutant flies showed activation of the Unfolded Protein Response (UPR) and presented inflammation and neuroinflammation that culminated in development of a neuronopathic disease. Treatment with ambroxol did not rescue GCase activity or reduce substrate accumulation; however, it ameliorated UPR, inflammation and neuroinflammation, and increased life span. Our results highlight the resemblance between the phenotype of the GBA1bm/m mutant fly and neuronopathic GD and underlie its relevance in further GD studies as well as a model to test possible therapeutic modalities.

2021-03-31 | GSE142144 | GEO

PKCγ-mediated phosphorylation of CRMP2 regulates dendritic outgrowth in cerebellar Purkinje cells

Project description:The signalling protein PKCγ is a major regulator of Purkinje cell development and synaptic function. We have shown previously that increased PKCγ activity impairs dendritic development of cerebellar Purkinje cells. Mutations in the protein kinase Cγ gene (PRKCG) cause spinocerebellar ataxia type 14 (SCA14). In a transgenic mouse model of SCA14 expressing the human S361G mutation, Purkinje cell dendritic development is impaired in cerebellar slice cultures similar to pharmacological activation of PKC. The mechanisms of PKCγ-driven inhibition of dendritic growth are still unclear. Using immunoprecipitation-coupled mass spectrometry analysis we have identified Collapsin Response Mediator Protein 2 (CRMP2) as a protein interacting with constitutive active PKCγ(S361G) and confirmed the interaction with the Duolink™ proximity ligation assay. We show that in cerebellar slice cultures from PKCγ(S361G)- mice, phosphorylation of CRMP2 at the known PKC target site Thr555 is increased in Purkinje cells confirming phosphorylation of CRMP2 by PKCγ. miRNA-mediated CRMP2 knockdown decreased Purkinje cell dendritic outgrowth in dissociated cerebellar cultures as did the transfection of CRMP2 mutants with a modified Thr555 site. In contrast, dendritic development was normal after wildtype CRMP2 overexpression. In a novel knock-in mouse expressing only the phospho-defective T555A-mutant CRMP2, Purkinje cell dendritic development was reduced in dissociated cultures. This reduction could be rescued by transfecting wildtype CRMP2 but only partially by the phospho-mimetic T555D-mutant. Our findings establish CRMP2 as an important target of PKCγ phosphorylation in Purkinje cells mediating its control of dendritic development. Dynamic regulation of CRMP2 phosphorylation via PKCγ is required for its correct function.

2022-02-24 | PXD020124 | Pride

Identification of a biomarker in cerebrospinal fluid for neuronopathic forms of Gaucher disease

Project description:Gaucher disease, a recessive inherited metabolic disorder caused by defects in the gene encoding glucosylceramidase (GlcCerase), can be divided into three subtypes according to the appearance of symptoms associated with central nervous system involvement. We now identify a protein, glycoprotein non-metastatic B (GPNMB), that acts as an authentic marker of brain pathology in neurological forms of Gaucher disease. Using three independent techniques, including quantitative global proteomic analysis of cerebrospinal fluid (CSF) in samples from Gaucher disease patients that display neurological symptoms, we demonstrate a correlation between the severity of symptoms and GPNMB levels. Moreover, GPNMB levels in the CSF correlate with disease severity in a mouse model of Gaucher disease. GPNMB was also elevated in brain samples from patients with type 2 and 3 Gaucher disease. Our data suggest that GPNMB can be used as a marker to quantify neuropathology in Gaucher disease patients and as a marker of treatment efficacy once suitable treatments towards the neurological symptoms of Gaucher disease become available.

2016-06-24 | PXD001654 | Pride

Global Gene Expression Profiles in Cultured Skin Fibroblasts Derived from Patients with Gaucher Disease

Project description:This work presents the discovery of genes that are dysregulated in patients with Type I and Type III Gaucher Disease. It provides insight into the unique pathogenesis of these phenotypes, improved diagnostic accuracy and potential novel therapies for these patients. Control and patient fibroblast cultures were established from full-thickness, skin biopsies obtained under a protocol approved by the IRB of the National Institute of Neurological Disorders and Stroke. Patient cultures were homoallelic for either the N370S mutation (non-neuronopathic, Gaucher Disease Type I, n=5), the L444P mutation (neuronopathic, Gaucher Disease Type III, n=5), or Wild-Type (Control, n=4).

2010-06-08 | E-GEOD-21899 | biostudies-arrayexpress

Human Cerebellar Organoids with functional Purkinje Cells

Project description:Human Cerebellar Organoids with functional Purkinje Cells

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Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease

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

2020-11-08 | GSE157992 | GEO