Role of Microglia in Ataxias

Ferro, Austin; Sheeler, Carrie; Rosa, Juao-Guilherme; Cvetanović, Marija

doi:10.1016/j.jmb.2019.01.016

Cited by 33 publications

(15 citation statements)

References 112 publications

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“…Of note, Bergmann glial cells showed a strong reaction in places with missing Purkinje cells. Likewise, microglia frequently transforms into an activated state during cerebellar ataxia 18 . Activation leads to increases in microglial density, ramification, and elevated expression of ionized calcium-binding adapter molecule 1 (IBA1) ultimately triggering neuroinflammation 19 .…”

Section: Resultsmentioning

confidence: 99%

Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis

et al. 2020

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ACBD5 deficiency is a novel peroxisome disorder with a largely uncharacterized pathology. ACBD5 was recently identified in a tethering complex mediating membrane contacts between peroxisomes and the endoplasmic reticulum (ER). An ACBD5-deficient mouse was analyzed to correlate ACBD5 tethering functions with the disease phenotype. ACBD5-deficient mice exhibit elevated very long-chain fatty acid levels and a progressive cerebellar pathology. Liver did not exhibit pathologic changes but increased peroxisome abundance and drastically reduced peroxisome-ER contacts. Lipidomics of liver and cerebellum revealed tissue-specific alterations in distinct lipid classes and subspecies. In line with the neurological pathology, unusual ultra-long chain fatty acids (C > 32) were elevated in phosphocholines from cerebelli but not liver indicating an organ-specific imbalance in fatty acid degradation and elongation pathways. By contrast, ether lipid formation was perturbed in liver towards an accumulation of alkyldiacylglycerols. The alterations in several lipid classes suggest that ACBD5, in addition to its acyl-CoA binding function, might maintain peroxisome-ER contacts in order to contribute to the regulation of anabolic and catabolic cellular lipid pathways.

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Section: Resultsmentioning

confidence: 99%

Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis

et al. 2020

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“… 55 , 56 Significant glial activation has been described in post-mortem histology of various ataxias. 51 It has been studied most extensively in SCA1 patients 57 , 58 and likely plays an important role in the pathogenesis of SCA1. 10 In mouse models of SCA1, activation of microglia occurred early in the disease and was present prior to neuronal cell death.…”

Section: Discussionmentioning

confidence: 99%

Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias

Deistung

Thieme

Münchau

et al. 2022

Brain Communications

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The cerebellar nuclei are a brain region with high iron content. Surprisingly little is known about iron content in the cerebellar nuclei and its possible contribution to pathology in cerebellar ataxias, with the only exception of Friedreich’s ataxia. In the present exploratory cross-sectional study, quantitative susceptibility mapping was used to investigate volume, iron concentration and total iron content of the dentate nuclei in common types of hereditary and non-hereditary degenerative ataxias. Seventy-nine patients with spinocerebellar ataxias of type 1 (SCA1), 2 (SCA2), 3 (SCA3) and 6 (SCA6), fifteen patients with Friedreich’s ataxia, eighteen patients with multiple system atrophy, cerebellar type (MSA-C), and one hundred eleven healthy controls were included. All underwent 3T-MRI and clinical assessments. For each specific ataxia subtype, voxel-based and volumes-of-interest-based group analyses were performed in comparison to a corresponding age- and sex-matched control group, both for volume, magnetic susceptiblity (indicating iron concentration) and susceptibility mass (indicating total iron content) of the dentate nuclei. SCA1 and MSA-C patients showed higher susceptibilities in large parts of the dentate nucleus but unaltered susceptibility masses compared to controls. Friedreich’s ataxia patients and, only on a trend level, SCA2 patients showed higher susceptibilities in more circumscribed parts of the dentate. In contrast, SCA6 patients revealed lower susceptibilities and susceptibility masses compared to controls throughout the dentate nucleus. SCA3 patients showed no significant changes in susceptibility and susceptibility mass. Lower volume of the dentate nuclei was found to varying degrees in all ataxia types. It was most pronounced in SCA6 patients and least prominent in SCA3 patients. The findings show that alterations in susceptibility revealed by quantitative susceptibiltiy mapping are common in the dentate nuclei in different types of cerebellar ataxias. The most striking changes in susceptibility were found in SCA1, MSA-C, and SCA6. Because iron content is known to be high in glial cells but not in neurons of the cerebellar nuclei, the higher susceptibility in SCA1 and MSA-C may be explained by a reduction of neurons (increase in iron concentration) and/or an increase in iron-rich glial cells, e.g. microgliosis. Hypomyelination also leads to higher susceptibility and could also contribute. The lower susceptibility in SCA6 suggests a loss of iron-rich glial cells. Quantitative susceptibility maps warrant future studies of iron content and iron-rich cells in ataxias to gain a more comprehensive understanding of the pathogenesis of these diseases.

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“…The role of the cerebellar microglia in SCA pathogenesis was recently described in a comprehensive review by Ferro et al [167]. The microglia is a type of neuroglia representing the macrophage cells of the central nervous system.…”

Section: Role Of Microgliamentioning

confidence: 99%

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

Egorova

Bezprozvanny

2019

Neurotherapeutics

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The effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment. A better understanding of the uncovered molecular mechanisms of the disease allowed the scientific community to develop strategies of potential therapy and helped to create some promising therapeutic approaches for SCA2 treatment. Recent progress in this field will be discussed in this review article.

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Role of Microglia in Ataxias

Cited by 33 publications

References 112 publications

Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis

Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis

Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

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