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Ronin expression induces ataxia and cerebellar degeneration in a mouse model of ataxia

ABSTRACT: Ronin expression induces ataxia and cerebellar degeneration in a mouse model of ataxia

PROVIDER: PRJNA736487 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14773929_1.fastq.gz	Fastqsanger.gz
	SRR14773929_2.fastq.gz	Fastqsanger.gz
	SRR14773930_1.fastq.gz	Fastqsanger.gz
	SRR14773930_2.fastq.gz	Fastqsanger.gz
	SRR14773931_1.fastq.gz	Fastqsanger.gz

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Ronin expression induces ataxia and cerebellar degeneration in a mouse model of ataxia

Project description:Gene expression studies in cerebella isolated from 5 week old wildtype or transgenic mice (C57BL/6) overexpressing Ronin in Purkinje cells were generated. RNA was isolated from cerebella of 3 transgenic animals at 5 weeks of agee and 3 wildtype litter mates.

2021-06-10 | GSE176518 | GEO

Ronin overexpression induces cerebellar degeneration in a mouse model of ataxia.

Project description:Spinocerebellar ataxias (SCAs) are a group of genetically heterogeneous inherited neurodegenerative disorders characterized by progressive ataxia and cerebellar degeneration. Here, we used a mouse model to test a possible connection between SCA and Ronin (Thap11), a polyglutamine-containing transcriptional regulator encoded in a region of human chromosome 16q22.1 that has been genetically linked to SCA type 4. We report that transgenic expression of Ronin in mouse cerebellar Purkinje cells leads to detrimental loss of these cells and the development of severe ataxia as early as 10 weeks after birth. Mechanistically, we find that several SCA-causing genes harbor Ronin DNA-binding motifs and are transcriptionally deregulated in transgenic animals. In addition, ectopic expression of Ronin in embryonic stem cells significantly increases the protein level of Ataxin-1, the protein encoded by Atxn1, alterations of which cause SCA type 1. This increase is also seen in the cerebellum of transgenic animals, although the latter was not statistically significant. Hence, our data provide evidence for a link between Ronin and SCAs, and suggest that Ronin may be involved in the development of other neurodegenerative diseases.

| S-EPMC8246265 | biostudies-literature

Ataxia-telangiectasia cerebellar cortex expression

Project description:Cerebellar cortex expression in ataxia-telangiectasia patients and normal controls. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency. Human frozen tissue was obtained from the NICHD Brain and Tissue Bank of Developmental Disorders at the University of Maryland, Baltimore, MD. RNA was prepared and run on an Illumina Human HT-12 v4 microarray. 3 ataxia-telangiectasia (A-T) cases and 4 normal controls.

2015-10-30 | E-GEOD-61019 | biostudies-arrayexpress

Cerebellar ataxia cases - samples

Project description:Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) samples

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Ataxia-telangiectasia cerebellar cortex expression

2015-10-30 | GSE61019 | GEO

WWOX P47T loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration

Project description:WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12). This mutation affects the WW1 protein binding domain of WWOX, impairing its ability to interact with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T that phenocopies SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination. These deficits progressed with age, and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice exhibited signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. The cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions from these Wwox LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation and severe cerebellar dysfunction, activation of pathways compatible with compensatory neurogenesis along with major suppression of gene networks associated with neuronal cell differentiation and brain development. Our results show significant pathobiological effects and potential mechanisms through which Wwox LoF leads to cerebellar neurodegeneration, neuroinflammation, and ataxia.

2023-02-28 | GSE215425 | GEO

Metabolome analysis in the diagnosis of childhood cerebellar ataxia

Project description:Metabolome studies to aid in the diagnosis and molecular elucidation of a child presenting chronic progressive cerebellar ataxia and an undiagnosed condition.

2020-10-20 | ST001518 | MetabolomicsWorkbench

Epigenetic dysregulation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7

Project description:Epigenetic dysregulation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7

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WWOX P47T loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration

Project description:WWOX P47T loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration

| PRJNA890254 | ENA

Cerebellar abiotrophy in working Kelpies with a later clinical onset

Project description:Australian working Kelpie dogs are known to be affected with an autosomal recessive form of inherited cerebellar ataxia (cerebellar abiotrophy, CA) that is characterised by a degeneration of Purkinje and granule cells in the cerebellar cortex. The clinical signs of CA include cerebellar ataxia, head tremor, motor in-coordination, wide based stance and high stepping gait, with varied clinical onset age. The clinical and pathological features are similar to cerebellar ataxias in humans. The genome-wide association study on a group of working Kelpies affected with the later onset form of CA identified a region on chromosome 9 to be strongly associated with the disease phenotype. Homozygosity analysis and whole genome sequencing identified a missense single nucleotide polymorphism, that segregated with the CA phenotype.

2022-12-31 | GSE102154 | GEO

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