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The leukodystrophies are a family of heritable disorders characterised by white matter degeneration, accompanied by variable clinical symptoms including loss of motor function and cognitive decline. Now thought to include over 50 distinct disorders, there are a vast array of mechanisms underlying the pathology of these monogenic conditions and, acc...
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Background. Affecting 60% of the people diagnosed with dementia, Alzheimer's disease is a neurodegenerative pathology that negatively impacts the cognitive function. It is characterised by symptoms as memory loss, locomotor difficulties, behavioural changes, and even rationalization issues. This disease has been studied on both rodents and fishes....
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... The leukodystrophies are a family of more than 50 distinct heritable central nervous system (CNS) disorders characterized by diminished cerebral and cerebellar white matter due to dysregulated myelin formation or degeneration 14 . HLD is rare, but comprises the single largest category among undiagnosed genetic leukodystrophies, which collectively impacts~1 in 7500 live births, representing a major group of neurodevelopmental disorders 15 . ...
... Bottom row (Sibling 2 at 8 yr): Sagittal T1 (13) reveals persistently thin CC with loss of splenium myelin (arrow). Frontal lobe white matter (*) is lower in signal on T1 axial (14), and unchanged on axial FLAIR (15) and coronal T2 (16) images. PLIC signal abnormality is unchanged. ...
... PLIC signal abnormality is unchanged. ALIC has lost myelin signal on T1 (14), FLAIR (15), and T2 (16) weighted images. c Sanger sequencing of DNA isolated from immortalized LCLs generated from unaffected control 3 (left), carrier parent (center), and affected sibling (right). ...
Hypomyelinating leukodystrophy (HLD) is an autosomal recessive disorder characterized by defective central nervous system myelination. Exome sequencing of two siblings with severe cognitive and motor impairment and progressive hypomyelination characteristic of HLD revealed homozygosity for a missense single-nucleotide variant (SNV) in EPRS1 (c.4444 C > A; p.Pro1482Thr), encoding glutamyl-prolyl-tRNA synthetase, consistent with HLD15. Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA. Variant mRNA exhibits reduced METTL3 methyltransferase-mediated writing of N⁶-methyladenosine (m⁶A) and reduced reading by YTHDC1 and YTHDF1/3 required for efficient mRNA nuclear export and translation, respectively. In contrast to current models, the variant does not alter the sequence of m⁶A target sites, but instead reduces their accessibility for modification. The defect was rescued by antisense morpholinos predicted to expose m⁶A sites on target EPRS1 mRNA, or by m⁶A modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor. Our bioinformatic analysis predicts widespread occurrence of SNVs associated with human health and disease that similarly alter accessibility of distal mRNA m⁶A sites. These results reveal a new RNA-dependent etiologic mechanism by which SNVs can influence gene expression and disease, consequently generating opportunities for personalized, RNA-based therapeutics targeting these disorders.
... The development of animal models to study neurodevelopmental disorders, including leukodystrophies, in vivo has been invaluable for testing therapies [47][48][49][50]. However, many rodent models fail to recapitulate key aspects of the human disease or are embryonic lethal [51]. Supv3l1 knockout in mice, for example, results in embryonic lethality, with further investigation identifying a role for SUV3 in the cytoplasm to suppress mitotic homologous recombination [34]. ...
We describe eighteen individuals from twelve families with an autosomal recessive neurodevelopmental disorder and variable leukodystrophy harbouring biallelic variants in SUPV3L1. SUPV3L1 encodes the RNA helicase SUV3 (also known as SUPV3L1), with previous studies demonstrating a role for the protein as part of the mitochondrial degradosome. Patient mutations result in an accumulation of mitochondrial double stranded RNAs in human cells. An assessment of supv3l1 knock-out zebrafish confirmed the role of supv3l1 in neurodevelopment, with gross defects identified in mitochondrial biogenesis and microglial function. Zebrafish displayed a significant activation of the type 1 interferon pathway, which was supported by qPCR of blood RNA from four patients with biallelic SUV3 mutations. Altogether, we describe a clinico-radiological spectrum associated with biallelic SUPV3L1 mutations, demonstrating that loss of SUV3 function results in altered mitochondrial biogenesis, increased mitochondrial double stranded RNA, dysplastic microglia and activation of the type 1 interferon innate immune pathway.
... 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 have no models, and the animal models that have been generated often show no or mixed recapitulation of key phenotypes (reviewed by Rutherford & Hamilton, 2019). For example, of the mouse models, only some show key phenotypes, and the severity of symptoms is relatively mild as compared to humans with typically a longer time course to phenotype (Rutherford & Hamilton, 2019). ...
... Many leukodystrophies have no models, and the animal models that have been generated often show no or mixed recapitulation of key phenotypes (reviewed by Rutherford & Hamilton, 2019). For example, of the mouse models, only some show key phenotypes, and the severity of symptoms is relatively mild as compared to humans with typically a longer time course to phenotype (Rutherford & Hamilton, 2019). ...
... Previous review articles have summarized some of the zebrafish models for leukodystrophy, through 2021 (Berdowski et al., 2021;Rutherford et al., 2021;Rutherford & Hamilton, 2019). Here, we provide updates and focus specifically on zebrafish topics and disease models for leukodystrophy (Table 1) which were not addressed in these previous reviews. ...
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.
... Leukodystrophy is a group of related genetic disorders characterized by white matter degeneration that leads to a variety of symptoms including loss of motor function and cognitive decline (Parikh et al., 2015;Kevelam et al., 2016;Rutherford and Hamilton, 2019). It is estimated that there is over 50 different LDs caused by various monogenic mutations, with X-linked adrenoleukodystrophy (X-ALD), metachromatic LD (MLD), Krabbe disease (KD), Alexander disease (AD), and Aicardi-Goutieres syndrome (AGS) being the most common LDs (Stellitano et al., 2016). ...
... Although some animal models of LD can recapitulate aspects of the human pathophysiology observed in LD patients, many of these models fail to encompass important aspects of this human disease. Depending on the model, the timing of demyelination could be delayed or not occur at all, and generation of myelin phenotypes requires complete knockout of the gene of interest, which is not equivalent to the human genetics of LD (Rutherford and Hamilton, 2019). Fortunately, several studies using hiPSC-derived models of LD appear to be effectively overcoming these issues of face and construct validity present in animal models of LD. ...
Oligodendrocytes play a crucial role in our central nervous system (CNS) by myelinating axons for faster action potential conduction, protecting axons from degeneration, structuring the position of ion channels, and providing nutrients to neurons. Oligodendrocyte dysfunction and/or dysmyelination can contribute to a range of neurodegenerative diseases and neuropsychiatric disorders such as Multiple Sclerosis (MS), Leukodystrophy (LD), Schizophrenia (SCZ), and Autism Spectrum Disorder (ASD). Common characteristics identified across these disorders were either an inability of oligodendrocytes to remyelinate after degeneration or defects in oligodendrocyte development and maturation. Unfortunately, the causal mechanisms of oligodendrocyte dysfunction are still uncertain, and therapeutic targets remain elusive. Many studies rely on the use of animal models to identify the molecular and cellular mechanisms behind these disorders, however, such studies face species-specific challenges and therefore lack translatability. The use of human induced pluripotent stem cells (hiPSCs) to model neurological diseases is becoming a powerful new tool, improving our understanding of pathophysiology and capacity to explore therapeutic targets. Here, we focus on the application of hiPSC-derived oligodendrocyte model systems to model disorders caused by oligodendrocyte dysregulation.
... This study's purpose was to find future treatments for leukodystrophies by reviewing animal models of these disorders [26]. According to the findings, these models have widespread flaws in the existing literature. ...
... Leukodystrophies and related illnesses are better understood because of the works reviewed here. In order to create effective treatments, they stress the significance of comprehending the underlying mechanisms [26]. As a potential treatment for disappearing white matter disorder, research into altering eIF2B activity is encouraging [27]. ...
The elderly often suffer from "mild" dementia due to white matter disease, which is another name for repeated brain infarctions. The degeneration of white matter, which links various parts of the brain to the spinal cord, is the root cause of this disorder, which develops with age. Dementia, imbalance, and movement problems are symptoms of this degenerative disease that worsen with age. This research’s goal is to study current therapy options and identify methods for early diagnosis of white matter illness. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for meta-analyses and systematic reviews served as the basis for our literature review. Results from the search in ScienceDirect and Medline/Pubmed led to the finalization of 33 studies. The complex relationship between white matter hyperintensities (WMHs) and neurological disorders is the subject of this comprehensive review, which sheds light on the varied terrain of WMH studies by highlighting their consequences and developing evaluation techniques.
... One family of white matter diseases in which the contribution of microglia is becoming more apparent are the leukodystrophies -a family of monogenic white matter disorders, many of which present during infancy [27,46]. These devastating conditions are associated with extensive psychomotor impairment, the formation of white matter lesions, neuroinflammation and, in many cases, limited life expectancy. ...
RNaseT2-deficient leukodystrophy is a rare infantile white matter disorder mimicking a viral infection and resulting in severe psychomotor impairments. Despite its severity, there remain no treatments for this disorder, with little understanding of cellular mechanisms of pathogenesis. Recent research using the rnaset2 mutant zebrafish model has suggested that microglia – brain-resident phagocytes – may be the drivers of neuroinflammation in this disorder, due to their failure to digest apoptotic debris during early development. As such, the current study aimed to develop a strategy for microglial replacement and test the effects of this intervention on rnaset2 mutant zebrafish pathology. We developed a strategy for microglial replacement through transplantation of adult whole kidney marrow-derived macrophages into embryonic hosts. Using live imaging, we revealed that transplant-derived macrophages can engraft within host brains and express microglia-specific markers, suggesting adoption of a microglial phenotype. Tissue clearing strategies revealed the persistence of transplanted cells in host brains beyond embryonic stages We demonstrated that transplanted cells clear apoptotic cells within the brain, as well as rescuing overactivation of the antiviral response otherwise seen in mutant larvae. RNA sequencing at the point of peak transplant-derived cell engraftment confirms that transplantation can reduce the brain-wide immune response, and particularly the antiviral response, in rnaset2 -deficient brains. Crucially, this reduction in neuroinflammation resulted in behavioural rescue - restoring rnaset2 mutant motor activity to wild type levels in embryonic and juvenile stages. Together, these findings demonstrate the role of microglia as the cellular drivers of neuropathology in rnaset2 mutants, and that macrophage transplantation is a viable strategy for microglial replacement in the zebrafish. Therefore, microglia-targeted interventions may have therapeutic benefits in RNaseT2-deficient leukodystrophy.
... Zebrafish are a popular research model for studying neurological diseases, such as Parkinson's, multiple sclerosis, leukodystrophies and epilepsy. [1][2][3][4][5][6] Most of the work into these neurological conditions is conducted on transparent juvenile fish, which are amenable to real-time optical imaging techniques. However, longitudinal monitoring of disease progression is visually limited by the opacity of adult zebrafish restricting the scope of data collection at these later stages. ...
Zebrafish (Danio rerio) has been successfully used for decades in developmental studies and disease modelling. The remarkable uptake of zebrafish as a model system is partly due to its transparency during the early weeks of its development, allowing in vivo imaging of cellular and molecular processes. However, this key advantage wears off when tissues become opaque as the animal reaches juvenile and adult stages, rendering access to tissues for live imaging and longitudinal studies difficult. Here we provided a novel approach to image and assess tissue integrity of adult zebrafish using Magnetic Resonance Imaging (MRI) on live zebrafish suitable for longitudinal studies. We built a 3D‐printed life support chamber and designed a protocol‐directed sedation regime to recover adult zebrafish post scanning in a 9.4T MRI scanner. Our life support chamber is cheap and easy to create using 3D printing, allowing other groups to copy our template for quick setup. Additionally, we optimised the delivery of contrast agent to enhance brain signals in order to refine current delivery, usually delivered intravenously in rodents. We show here that immersion in gadolinium was a viable alternative to intraperitoneal injection to reduce T1 relaxation times. This resulted in protocol refinement as per the 3Rs guidelines and improved image contrast in adult zebrafish disease models. In conclusion, we provide here a detailed methodology to allow longitudinal studies of brain tissue integrity of adult zebrafish, combining safe and efficient delivery of contrast agent and live MRI. This technique can be used to bridge the gap between in vivo studies and longitudinal brain analysis in adult zebrafish which can be applied to the ever‐growing number of adult zebrafish models of ageing and neurodegenerative diseases.
... One of the main bottlenecks hampering RD research progresses is the difficulty to generate relevant experimental models where studying disease molecular pathogenesis. Since pathological brain tissue is not easily accessible, most of these researches have been carried out on animal models, mainly engineered rodents (knock-out or knock-in and cells derived from them), and sometimes zebrafish, to recapitulate the human pathologies [31]. Although these animal models have been essential for the elucidation of some aspects of astrocyte physiopathology, they showed some limits. ...
Astrocytes are very versatile cells, endowed with multitasking capacities to ensure brain homeostasis maintenance from brain development to adult life. It has become increasingly evident that astrocytes play a central role in many central nervous system pathologies, not only as regulators of defensive responses against brain insults but also as primary culprits of the disease onset and progression. This is particularly evident in some rare leukodystrophies (LDs) where white matter/myelin deterioration is due to primary astrocyte dysfunctions. Understanding the molecular defects causing these LDs may help clarify astrocyte contribution to myelin formation/maintenance and favor the identification of possible therapeutic targets for LDs and other CNS demyelinating diseases. To date, the pathogenic mechanisms of these LDs are poorly known due to the rarity of the pathological tissue and the failure of the animal models to fully recapitulate the human diseases. Thus, the development of human induced pluripotent stem cells (hiPSC) from patient fibroblasts and their differentiation into astrocytes is a promising approach to overcome these issues. In this review, we discuss the primary role of astrocytes in LD pathogenesis, the experimental models currently available and the advantages, future evolutions, perspectives, and limitations of hiPSC to study pathologies implying astrocyte dysfunctions.
... Contrary to mice, the loss of oligodendrocytes and myelin in zebrafish is promising for ccALD phenotype modeling; however, only a modest increase in VLCFAs and no change in cortisol expression was observed (Strachan et al., 2017). Additionally, the adaptive immune system, a key element in the etiopathogenesis of ccALD, matures in zebrafish only 14 days postfertilization (Rutherford & Hamilton, 2019), while the above findings were seen 3-8 days postfertilization. This may suggest a nonimmunologic role for Abcd1 in oligodendrocyte maintenance. ...
X‐linked adrenoleukodystrophy (X‐ALD) is a phenotypically heterogeneous disorder involving defective peroxisomal β‐oxidation of very long‐chain fatty acids (VLCFAs), due to mutation in the ABCD1 gene. X‐ALD is the most common peroxisomal inborn error of metabolism and confers a high degree of morbidity and mortality. Remarkably, a subset of patients exhibit a cerebral form with inflammatory invasion of the central nervous system and extensive demyelination, while in others only dying‐back axonopathy or even isolated adrenal insufficiency is seen, without genotype–phenotype correlation. X‐ALD's biochemical signature is marked elevation of VLCFAs in blood, a finding that has been utilized for massive newborn screening for early diagnosis. Investigational gene therapy approaches hold promises for improved outcomes. However, the pathophysiological mechanisms of the disease remain poorly understood, limiting investigation of targeted therapeutic options. Animal models for the disease recapitulate the biochemical signature of VLCFA accumulation and demonstrate mitochondrially generated reactive oxygen species, oxidative damage, increased glial death, and axonal damage. Most strikingly, however, cerebral invasion of leukocytes and demyelination were not observed in any animal model for X‐ALD, reflecting upon pathological processes that are yet to be discovered. This review summarizes the current disease models in animals, the lessons learned from these models, and the gaps that remained to be filled in order to assist in therapeutic investigations for ALD.
... With over 70% of genes shared with humans and carrying orthologs of ∼82% of human disease-associated genes, and continuously improving genetic tools, the zebrafish is an increasingly popular model for investigating genetic disorders (Howe et al., 2013). For more information, please see extensive reviews by Duncan et al. (2011), Ackerman and Monk (2016) and Rutherford and Hamilton (2019) on zebrafish and rodent models of leukodystrophies and myelination. ...
... The zebrafish has repeatedly proven its value as a system for unparalleled developmental observations of in vivo cellular mechanisms, and its many unique advantages readily complement data obtained through other model systems (Box 2). Especially for understanding the highly interactive cellular processes of myelination and glial cell development in leukodystrophy, the ability to perform real-time, unbiased and non-invasive imaging of dynamic cellular interactions during early embryonic development in a whole organism makes the zebrafish a promising model that can take the field far beyond the current knowledge (Rutherford and Hamilton, 2019;Keefe et al., 2020). 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). ...
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.
