Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Astroglia contribute to the pathogenesis of spinocerebellar ataxia Type 1 (SCA1) in a biphasic, stage-of-disease specific manner.

ABSTRACT: Spinocerebellar ataxia type 1 (SCA1) is a fatal, dominantly inherited neurodegenerative disease caused by the expansion of CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by balance and coordination deficits due to the predominant loss of Purkinje neurons in the cerebellum. We previously demonstrated that cerebellar astrogliosis beings during the early stages of SCA1, prior to onset of motor deficits and loss of Purkinje neurons. We communicate here that cerebellar astrogliosis contributes to SCA1 pathogenesis in a biphasic, stage of disease dependent manner. We modulated astrogliosis by selectively reducing pro-inflammatory transcriptional regulator nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling in astroglia via a Cre-lox mouse genetic approach. Our results indicate that inhibition of astroglial NF-κB signaling, prior to motor deficit onset, exacerbates disease severity. This is suggestive of a neuroprotective role mediated by astroglia during early stage SCA1. In contrast, inhibition of astroglial NF-κB signaling during late stage of disease ameliorated motor deficits, indicating a potentially harmful role of astroglia late in SCA1. These results indicate that astrogliosis may have a critical and dual role in disease. If so, our results imply that anti-inflammatory astroglia-based therapeutic approaches may need to consider disease progression to achieve therapeutic efficacy.

SUBMITTER: Kim JH

PROVIDER: S-EPMC8049102 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Post-symptomatic Delivery of Brain-Derived Neurotrophic Factor (BDNF) Ameliorates Spinocerebellar Ataxia Type 1 (SCA1) Pathogenesis.

Project description:Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an abnormal expansion of CAG repeats in the Ataxin1 (ATXN1) gene. SCA1 is characterized by motor deficits, cerebellar neurodegeneration, and gliosis and gene expression changes. Expression of brain-derived neurotrophic factor (BDNF), growth factor important for the survival and function of cerebellar neurons, is decreased in ATXN1[82Q] mice, the Purkinje neuron specific transgenic mouse model of SCA1. As this decrease in BDNF expression may contribute to cerebellar neurodegeneration, we tested whether delivery of extrinsic human BDNF via osmotic ALZET pumps has a beneficial effect on disease severity in this mouse model of SCA1. Additionally, to test the effects of BDNF on established and progressing cerebellar pathogenesis and motor deficits, we delivered BDNF post-symptomatically. We have found that post-symptomatic delivery of extrinsic BDNF ameliorated motor deficits and cerebellar pathology (i.e., dendritic atrophy of Purkinje cells, and astrogliosis) indicating therapeutic potential of BDNF even after the onset of symptoms in SCA1. However, BDNF did not alter Purkinje cell gene expression changes indicating that certain aspects of disease pathogenesis cannot be ameliorated/slowed down with BDNF and that combinational therapies may be needed.

| S-EPMC8217121 | biostudies-literature

Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model.

Project description:Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine tract expansion. In SCA1, the expanded polyglutamine tract is in the ataxin-1 (ATXN1) protein. ATXN1 is part of an in vivo complex with retinoid acid receptor-related orphan receptor alpha (Rora) and the acetyltransferase tat-interactive protein 60 kDa (Tip60). ATXN1 and Tip60 interact directly via the ATXN1 and HMG-box protein 1 (AXH) domain of ATXN1. Moreover, the phospho-mimicking Asp amino acid at position 776, previously shown to enhance pathogenesis, increases the ability of ATXN1 to interact with Tip60. Using a genetic approach, the biological relevance of the ATXN1/Tip60 interaction was assessed by crossing ATXN1[82Q] mice with Tip60(+/-)animals. Partial Tip60 loss increased Rora and Rora-mediated gene expression and delayed ATXN1[82]-mediated cerebellar degeneration during mid-stage disease progression. These results suggested a specific, temporal role for Tip60 during disease progression. We also showed that genetic background modulated ATXN1[82Q]-induced phenotypes. Of interest, these latter studies showed that some phenotypes are enhanced on a mixed background while others are suppressed.

| S-EPMC3090197 | biostudies-other

Brain Derived Neurotrophic Factor (BDNF) Delays Onset of Pathogenesis in Transgenic Mouse Model of Spinocerebellar Ataxia Type 1 (SCA1).

Project description:Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an abnormal expansion of CAG repeats in the Ataxin-1 (ATXN1) gene and characterized by motor deficits and cerebellar neurodegeneration. Even though mutant ATXN1 is expressed from an early age, disease onset usually occurs in patient's mid-thirties, indicating the presence of compensatory factors that limit the toxic effects of mutant ATXN1 early in disease. Brain derived neurotrophic factor (BDNF) is a growth factor known to be important for the survival and function of cerebellar neurons. Using gene expression analysis, we observed altered BDNF expression in the cerebella of Purkinje neuron specific transgenic mouse model of SCA1, ATXN1[82Q] mice, with increased expression during the early stage and decreased expression in the late stage of disease. We therefore investigated the potentially protective role of BDNF in early stage SCA1 through intraventricular delivery of BDNF via ALZET osmotic pumps. Extrinsic BDNF delivery delayed onset of motor deficits and Purkinje neuron pathology in ATXN1[82Q] mice supporting its use as a novel therapeutic for SCA1.

| S-EPMC6348256 | biostudies-literature

Mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of spinocerebellar ataxia type 12 (SCA12).

Project description:Spinal cerebellar ataxia type 12 (SCA12) has been attributed to the elevated expression of ppp2r2b. To better elucidate the pathomechanism of the neuronal disorder and to search for a pharmacological treatment, Drosophila models of SCA12 were generated by overexpression of a human ppp2r2b and its Drosophila homolog tws. Ectopic expression of ppp2r2b or tws caused various pathological features, including neurodegeneration, apoptosis, and shortened life span. More detailed analysis revealed that elevated ppp2r2b and tws induced fission of mitochondria accompanied by increases in cytosolic reactive oxygen species (ROS), cytochrome c, and caspase 3 activity. Transmission electron microscopy revealed that fragmented mitochondria with disrupted cristae were engulfed by autophagosomes in photoreceptor neurons of flies overexpressing tws. Additionally, transgenic flies were more susceptible to oxidative injury induced by paraquat. By contrast, ectopic Drosophila Sod2 expression and antioxidant treatment reduced ROS and caspase 3 activity and extended the life span of the SCA12 fly model. In summary, our study demonstrates that oxidative stress induced by mitochondrial dysfunction plays a causal role in SCA12, and reduction of ROS is a potential therapeutic intervention for this neuropathy.

| S-EPMC3122230 | biostudies-literature

Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.

Project description:SCA12 is a progressive autosomal-dominant disorder, caused by a CAG/CTG repeat expansion in PPP2R2B on chromosome 5q32, and characterized by tremor, gait ataxia, hyperreflexia, dysmetria, abnormal eye movements, anxiety, depression, and sometimes cognitive impairment. Neuroimaging has demonstrated cerebellar and cortical atrophy. We now present the neuropathology of the first autopsied SCA12 brain and utilize cell models to characterize potential mechanisms of SCA12 neurodegeneration.A fixed SCA12 brain was examined using gross, microscopic, and immunohistochemical methods. The effect of the repeat expansion on PPP2R2B B?1 expression was examined in multiple cell types by transient transfection of constructs containing the PPP2R2B B?1 promoter region attached to a luciferase reporter. The neurotoxic effect of PPP2R2B overexpression was examined in transfected rat primary neurons.Neuropathological investigation revealed enlarged ventricles, marked cerebral cortical atrophy and Purkinje cell loss, less-prominent cerebellar and pontine atrophy, and neuronal intranuclear ubiquitin-positive inclusions, consistent with Marinesco bodies, which did not stain for long polyglutamine tracts, alpha-synuclein, tau, or transactive response DNA-binding protein 43. Reporter assays demonstrated that the region of PPP2R2B containing the repeat functions as a promoter, and that promoter activity increases with longer repeat length and is dependent on cell type, repeat sequence, and sequence flanking the repeat. Overexpression of PPP2R2B in primary cortical neurons disrupted normal morphology.SCA12 involves extensive, but selective, neurodegeneration distinct from Alzheimer's disease, synucleinopathies, tauopathies, and glutamine expansion diseases. SCA12 neuropathology may arise from the neurotoxic effect of repeat-expansion-induced overexpression of PPP2R2B.

| S-EPMC5127409 | biostudies-literature

Expansion of CAG repeats in the spinocerebellar ataxia type 1 (SCA1) gene in idiopathic oligozoospermia patients.

Project description:The lengths of CAG repeats in two spinocerebellar ataxia genes, SCA1 and SCA3, were analyzed to determine whether such repeats exist in higher numbers in infertile males.Blood samples were collected from healthy controls, oligozoospermia patients, and azoospermia patients. DNA fragments containing target CAG repeats were amplified by PCR with template DNA purified from the blood samples. CAG repeats in PCR fragments were determined, using ABI PRISM 310 Gene Analyzer.In SCA1, the distribution of CAG repeats in oligozoospermic males was different from that of the control group: More alleles had a repeat number that exceeded 32. Conversely, for SCA3, the examined oligozoospermia and azoospermia patients exhibited no differences in distribution of CAG repeats in comparison with the control group.SCA1 in a subset of oligozoospermia patients has an increased number of CAG repeats.

| S-EPMC2719072 | biostudies-other

Spinocerebellar ataxia 1 (SCA1) in the Japanese in Hokkaido may derive from a single common ancestry.

Project description:Spinocerebellar ataxia 1 (SCA1) is caused by expansion of an unstable CAG triplet repeat located on the short arm of chromosome 6. Precise mapping has shown a positional relationship to closely linked markers in the order of D6S109-D6S274-D6S288-SCA1-AM10GA-D6S89+ ++-EDN1 from centromere to telomere. The haplotype which cosegregated with the disease was determined in 12 Japanese pedigrees with SCA1. Although the alleles of the SCA1 haplotype varied from pedigree to pedigree, depending on the distance from the SCA1 locus, the affected and presymptomatic subjects carried the same alleles at D6S288 and D6S274. All the families with SCA1 had migrated from either Miyagi or Yamagata Prefectures, neighbouring areas in the Tohoku District, the northern part of Honshu which is the main island of Japan. It seems highly likely that SCA1 in the Japanese, at least those residing in Hokkaido, derives from a single common ancestry.

| S-EPMC1051630 | biostudies-literature

BDNF is altered in a brain-region specific manner and rescues deficits in Spinocerebellar Ataxia Type 1.

Project description:Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, dominantly inherited neurodegenerative disease caused by the expanded polyQ tract in the protein ATAXIN1 (ATXN1) and characterized by progressive motor and cognitive impairments. There are no disease-modifying treatments or cures for SCA1. Brain-derived neurotrophic factor (BDNF) plays important role in cerebellar physiology and has shown therapeutic potential for cerebellar pathology in the transgenic mouse model of SCA1, ATXN1[82Q] line that overexpress mutant ATXN1 under a cerebellar Purkinje-cell-specific promoter. Here we demonstrate decreased expression of brain derived neurotrophic factor (BDNF) in the cerebellum and medulla of patients with SCA1. Early stages of disease seem most amenable to therapy. Thus, we next quantified Bdnf expression in Atxn1154Q/2Q mice, a knock-in mouse model of SCA1, during the early symptomatic disease stage in four clinically relevant brain regions: cerebellum, medulla, hippocampus and motor cortex. We found that during the early stages of disease, Bdnf mRNA expression is reduced in the hippocampus and cerebellum, while it is increased in the cortex and brainstem. Importantly, we observed that pharmacological delivery of recombinant BDNF improved motor and cognitive performance, and mitigated pathology in the cerebellum and hippocampus of Atxn1154Q/2Q mice. Our findings demonstrate brain-region specific deficiency of BDNF in SCA1 and show that reversal of low BDNF levels offers the potential for meaningful treatment of motor and cognitive deficits in SCA1.

| S-EPMC9969743 | biostudies-literature

Stage-dependent biomarker changes in spinocerebellar ataxia type 3.

Project description:Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed. We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI. Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia. The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.

| S-EPMC10168503 | biostudies-literature

On the identification of potential novel therapeutic targets for spinocerebellar ataxia type 1 (SCA1) neurodegenerative disease using EvoPPI3.

Project description:EvoPPI (http://evoppi.i3s.up.pt), a meta-database for protein-protein interactions (PPI), has been upgraded (EvoPPI3) to accept new types of data, namely, PPI from patients, cell lines, and animal models, as well as data from gene modifier experiments, for nine neurodegenerative polyglutamine (polyQ) diseases caused by an abnormal expansion of the polyQ tract. The integration of the different types of data allows users to easily compare them, as here shown for Ataxin-1, the polyQ protein involved in spinocerebellar ataxia type 1 (SCA1) disease. Using all available datasets and the data here obtained for Drosophila melanogaster wt and exp Ataxin-1 mutants (also available at EvoPPI3), we show that, in humans, the Ataxin-1 network is much larger than previously thought (380 interactors), with at least 909 interactors. The functional profiling of the newly identified interactors is similar to the ones already reported in the main PPI databases. 16 out of 909 interactors are putative novel SCA1 therapeutic targets, and all but one are already being studied in the context of this disease. The 16 proteins are mainly involved in binding and catalytic activity (mainly kinase activity), functional features already thought to be important in the SCA1 disease.

| S-EPMC10561075 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data