Zebrafish disease model of human RNASET2 deficient cystic leukoencephalopathy displays abnormalities in early microglia

Weber, Thomas; Schlotawa, Lars; Dosch, Roland; Hamilton, Noémie; Kaiser, J.; Schiller, S.; Wenske, Britta; Gärtner, Jutta; Henneke, Marco

doi:10.1242/bio.049239

Cited by 4 publications

(5 citation statements)

References 43 publications

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“…The rnaset2-deficient zebrafish develop white matter anomalies coinciding with signs of inflammatory lesions and glial scars in periventricular areas of the adult zebrafish brain (Haud et al, 2011). Further investigation in a second line of rna-set2-deficient zebrafish revealed unaffected OPCs at early time points but abnormal microglia with delayed phagocytic activity and lysosomal dysfunction as revealed by an increase in acidic compartments (Weber et al, 2020). The recently reported Rnaset2a Rnaset2b double knockout mouse model develops a neuroinflammatory response with infiltration of T cells and inflammatory monocytes into the gray and white matter and upregulation of IFN-stimulated genes (Kettwig et al, 2021).…”

Section: Aicardi-goutières Syndrome (Ags)mentioning

confidence: 97%

Progress in leukodystrophies with zebrafish

Shih,

Raas,

Bonkowsky

2024

Dev Growth Differ

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Inherited leukodystrophies are genetic disorders characterized by abnormal white matter in the central nervous system. Although individually rare, there are more than 400 distinct types of leukodystrophies with a cumulative incidence of 1 in 4500 live births. The pathophysiology of most leukodystrophies is poorly understood, there are treatments for only a few, and there is significant morbidity and mortality, suggesting a critical need for improvements in this field. A variety of animal, cell, and induced pluripotent stem cell‐derived models have been developed for leukodystrophies, but with significant limitations in all models. Many leukodystrophies lack animal models, and extant models often show no or mixed recapitulation of key phenotypes. Zebrafish (Danio rerio) have become increasingly used as disease models for studying leukodystrophies due to their early onset of disease phenotypes and conservation of molecular and neurobiological mechanisms. Here, we focus on reviewing new zebrafish disease models for leukodystrophy or models with recent progress. This includes discussion of leukodystrophy with vanishing white matter disease, X‐linked adrenoleukodystrophy, Zellweger spectrum disorders and peroxisomal disorders, PSAP deficiency, metachromatic leukodystrophy, Krabbe disease, hypomyelinating leukodystrophy‐8/4H leukodystrophy, Aicardi–Goutières syndrome, RNASET2‐deficient cystic leukoencephalopathy, hereditary diffuse leukoencephalopathy with spheroids‐1 (CSF1R‐related leukoencephalopathy), and ultra‐rare leukodystrophies. Zebrafish models offer important potentials for the leukodystrophy field, including testing of new variants in known genes; establishing causation of newly discovered genes; and early lead compound identification for therapies. There are also unrealized opportunities to use humanized zebrafish models which have been sparsely explored.

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Section: Aicardi-goutières Syndrome (Ags)mentioning

confidence: 97%

Progress in leukodystrophies with zebrafish

Shih,

Raas,

Bonkowsky

2024

Dev Growth Differ

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“…Human infantile-onset RNASET2 -deficient cystic leukoencephalopathy is a Mendelian disorder that mimics cytomegalovirus brain infection during fetal development, resulting in inflammatory brain lesions ( Figure 1 D). Weber et al utilized a zebrafish model deficient in RNASET2 to investigate the effects of a lack of this enzyme [ 81 ]. The authors observed that RNASET2 -deficient zebrafish larvae exhibited an increased number of microglia with abnormal morphology, often containing neuronal inclusions ( Figure 1 D) [ 81 ].…”

Section: T2 Rnases: Biological Rolesmentioning

confidence: 99%

“…Weber et al utilized a zebrafish model deficient in RNASET2 to investigate the effects of a lack of this enzyme [ 81 ]. The authors observed that RNASET2 -deficient zebrafish larvae exhibited an increased number of microglia with abnormal morphology, often containing neuronal inclusions ( Figure 1 D) [ 81 ]. Furthermore, they found enhanced lysosomal staining within specific populations of the myeloid cell lineage, including microglia.…”

Section: T2 Rnases: Biological Rolesmentioning

confidence: 99%

“…Furthermore, they found enhanced lysosomal staining within specific populations of the myeloid cell lineage, including microglia. This study offers valuable insights into the pathogenetic mechanisms underlying the prenatal onset of RNASET2 -deficient leukoencephalopathy in humans, establishing a connection between this lysosomal disorder and the innate immune system ( Figure 1 D) [ 81 ]. Additionally, it highlights the potential links between RNASET2 deficiency and other immune-related childhood encephalopathies such as Aicardi-Goutières syndrome (AGS).…”

Section: T2 Rnases: Biological Rolesmentioning

confidence: 99%

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The Potential Role of the T2 Ribonucleases in TME-Based Cancer Therapy

Campomenosi,

Mortara,

Bassani

et al. 2023

Biomedicines

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In recent years, there has been a growing interest in developing innovative anticancer therapies targeting the tumor microenvironment (TME). The TME is a complex and dynamic milieu surrounding the tumor mass, consisting of various cellular and molecular components, including those from the host organism, endowed with the ability to significantly influence cancer development and progression. Processes such as angiogenesis, immune evasion, and metastasis are crucial targets in the search for novel anticancer drugs. Thus, identifying molecules with “multi-tasking” properties that can counteract cancer cell growth at multiple levels represents a relevant but still unmet clinical need. Extensive research over the past two decades has revealed a consistent anticancer activity for several members of the T2 ribonuclease family, found in evolutionarily distant species. Initially, it was believed that T2 ribonucleases mainly acted as anticancer agents in a cell-autonomous manner. However, further investigation uncovered a complex and independent mechanism of action that operates at a non-cell-autonomous level, affecting crucial processes in TME-induced tumor growth, such as angiogenesis, evasion of immune surveillance, and immune cell polarization. Here, we review and discuss the remarkable properties of ribonucleases from the T2 family in the context of “multilevel” oncosuppression acting on the TME.

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“…The major players in leukodystrophies have been well-characterized in zebrafish (Herbomel et al, 1999;Peri and Nüsslein-Volhard, 2008;Oosterhof et al, 2017;Marisca et al, 2020;Park et al, 2002;Mu et al, 2019;Chen et al, 2020) and have led to major discoveries in the functions of glial cells and myelination (Mensch et al, 2015;Almeida et al, 2018;Djannatian et al, 2019;Appel, 2019, 2020;Marisca et al, 2020;Mu et al, 2019;Li et al, 2012). Indeed, a number of genetic zebrafish models have provided important data on the disease mechanisms of several leukodystrophies (Pant et al, 2019;Strachan et al, 2017), including the involvement of microglia in the early disease pathology of CSF1R-related leukodystrophy (Oosterhof et al, 2018(Oosterhof et al, , 2019 and RNASET2-related leukodystrophy (Haud et al, 2011;Hamilton et al, 2020;Weber et al, 2020), and the identification of possible therapeutic targets for the treatment of X-ALD (Raas et al, 2021).…”

Section: Aberrant Astrocytesmentioning

confidence: 99%

The multicellular interplay of microglia in health and disease: lessons from leukodystrophy

Berdowski

Sanderson

Ham

2021

Disease Models &Amp; Mechanisms

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Microglia are highly dynamic cells crucial for developing and maintaining lifelong brain function and health through their many interactions with essentially all cellular components of the central nervous system. The frequent connection of microglia to leukodystrophies, genetic disorders of the white matter, has highlighted their involvement in the maintenance of white matter integrity. However, the mechanisms that underlie their putative roles in these processes remain largely uncharacterized. Microglia have also been gaining attention as possible therapeutic targets for many neurological conditions, increasing the demand to understand their broad spectrum of functions and the impact of their dysregulation. In this Review, we compare the pathological features of two groups of genetic leukodystrophies: those in which microglial dysfunction holds a central role, termed ‘microgliopathies’, and those in which lysosomal or peroxisomal defects are considered to be the primary driver. The latter are suspected to have notable microglia involvement, as some affected individuals benefit from microglia-replenishing therapy. Based on overlapping pathology, we discuss multiple ways through which aberrant microglia could lead to white matter defects and brain dysfunction. We propose that the study of leukodystrophies, and their extensively multicellular pathology, will benefit from complementing analyses of human patient material with the examination of cellular dynamics in vivo using animal models, such as zebrafish. Together, this will yield important insight into the cell biological mechanisms of microglial impact in the central nervous system, particularly in the development and maintenance of myelin, that will facilitate the development of new, and refinement of existing, therapeutic options for a range of brain diseases.

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Zebrafish disease model of human RNASET2 deficient cystic leukoencephalopathy displays abnormalities in early microglia

Cited by 4 publications

References 43 publications

Progress in leukodystrophies with zebrafish

Progress in leukodystrophies with zebrafish

The Potential Role of the T2 Ribonucleases in TME-Based Cancer Therapy

The multicellular interplay of microglia in health and disease: lessons from leukodystrophy

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