Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response

Keefe, Matthew D.; Soderholm, Haille E.; Shih, Hung-Yu; Stevenson, Tamara J.; Glaittli, Kathryn A; Bowles, D. Miranda; Schöll, E; Colby, Samuel; Merchant, Samer; Hsu, Edward W.; Bonkowsky, Joshua L.

doi:10.7554/elife.56319

Cited by 18 publications

(22 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lithium also inhibits GSK3β. In a zebrafish VWM model, 30 lithium effects were promising, but safe doses in VWM mice appeared ineffective (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Therapy Trial Design in Vanishing White Matter

et al. 2022

Self Cite

View full text Add to dashboard Cite

Vanishing white matter (VWM) is a leukodystrophy caused by recessive variants in the genes EIF2B1-EIF2B5. It is characterized by chronic neurologic deterioration with superimposed stress-provoked episodes of rapid decline. Disease onset spans from the antenatal period through senescence. Age at onset predicts disease evolution for patients with early onset, whereas disease evolution is unpredictable for later onset; patients with infantile and early childhood onset consistently have severe disease with rapid neurologic decline and often early death, whereas patients with later onset have highly variable disease. VWM is rare, but likely underdiagnosed, particularly in adults. Apart from measures to prevent stressors that could provoke acute deteriorations, only symptomatic care is currently offered. With increased insight into VWM disease mechanisms, opportunities for treatment have emerged. EIF2B1-EIF2B5 encode the 5-subunit eukaryotic initiation factor 2B complex, which is essential for translation of mRNAs into proteins and is a principal regulator of the integrated stress response (ISR). ISR deregulation is central to VWM pathology. Targeting components of the ISR has proven beneficial in mutant VWM mouse models, and several drugs are now in clinical development. However, clinical trials in VWM pose considerable challenges: low numbers of known patients with VWM, unpredictable disease course for patients with onset after early childhood, absence of intermediate biomarkers, and novel first-in-human molecular targets. Given these challenges and considering the critical need to offer therapies, we have formulated recommendations for enhanced diagnosis, drug trial setup, and patient selection, based on our expert evaluation of molecular, laboratory, and clinical data.

show abstract

“…Lithium also inhibits GSK3β. In a zebrafish VWM model, 30 lithium effects were promising, but safe doses in VWM mice appeared ineffective (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Therapy Trial Design in Vanishing White Matter

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…The zebrafish has become a frequently used model organism to study cellular and molecular mechanisms in the central nervous system, including myelination (Pogoda et al, 2006;Lyons and Talbot, 2015;Ackerman and Monk, 2016;Czopka, 2016) and oligodendrocyte differentiation (Ravanelli et al, 2018;Marisca et al, 2020). Notwithstanding the increasing relevance of zebrafish in assessing the pathomechanisms of human myelin-related diseases (Pérez-Rius et al, 2019;Keefe et al, 2020;Tsata et al, 2020), proteomic approaches to zebrafish myelin have fallen behind evolving technical standards. For example, no study is available thus far that systematically approaches the entire zebrafish CNS myelin proteome.…”

Section: Introductionmentioning

confidence: 99%

Proteome Profile of Myelin in the Zebrafish Brain

Siems

Jahn

Hoodless

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The velocity of nerve conduction along vertebrate axons depends on their ensheathment with myelin. Myelin membranes comprise specialized proteins well characterized in mice. Much less is known about the protein composition of myelin in non-mammalian species. Here, we assess the proteome of myelin biochemically purified from the brains of adult zebrafish (Danio rerio), considering its increasing popularity as model organism for myelin biology. Combining gel-based and gel-free proteomic approaches, we identified > 1,000 proteins in purified zebrafish myelin, including all known constituents. By mass spectrometric quantification, the predominant Ig-CAM myelin protein zero (MPZ/P0), myelin basic protein (MBP), and the short-chain dehydrogenase 36K constitute 12%, 8%, and 6% of the total myelin protein, respectively. Comparison with previously established mRNA-abundance profiles shows that expression of many myelin-related transcripts coincides with the maturation of zebrafish oligodendrocytes. Zebrafish myelin comprises several proteins that are not present in mice, including 36K, CLDNK, and ZWI. However, a surprisingly large number of ortholog proteins is present in myelin of both species, indicating partial evolutionary preservation of its constituents. Yet, the relative abundance of CNS myelin proteins can differ markedly as exemplified by the complement inhibitor CD59 that constitutes 5% of the total zebrafish myelin protein but is a low-abundant myelin component in mice. Using novel transgenic reporter constructs and cryo-immuno electron microscopy, we confirm the incorporation of CD59 into myelin sheaths. These data provide the first proteome resource of zebrafish CNS myelin and demonstrate both similarities and heterogeneity of myelin composition between teleost fish and rodents.

show abstract

“…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).…”

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

View full text Add to dashboard Cite

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.

show abstract

Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response

Cited by 18 publications

References 49 publications

Therapy Trial Design in Vanishing White Matter

Therapy Trial Design in Vanishing White Matter

Proteome Profile of Myelin in the Zebrafish Brain

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

Contact Info

Product

Resources

About