The Rag-Ragulator Complex Regulates Lysosome Function and Phagocytic Flux in Microglia

Shen, Kimberle; Sidik, Harwin; Talbot, William S.

doi:10.1016/j.celrep.2015.12.055

Cited by 72 publications

(116 citation statements)

References 69 publications

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“…SD neuropathology includes microglial activation, and therefore we hypothesized that Hexb deficiency would affect microglial lysosomes. To visualize lysosomes in vivo we used lysotracker (LT) staining, which labels all acidic organelles including lysosomes, and to visualize microglia we used transgenic zebrafish in which GFP expression is driven by the mpeg1‐ promotor (Berg et al, ; Ellett, Pase, Hayman, Andrianopoulos, & Lieschke, ; Shen et al, ). At 4 dpf, although there were no major differences in microglial numbers, lysosomal compartments of hexb deficient microglia were found to be enlarged compared to those in controls, suggesting that Hexb deficiency results in lysosomal abnormalities in microglia (Figure c,d).…”

Section: Resultsmentioning

confidence: 99%

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Kuil

Martí

Mascaro

et al. 2019

Glia

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Sphingolipidoses are severe, mostly infantile lysosomal storage disorders (LSDs) caused by defective glycosphingolipid degradation. Two of these sphingolipidoses, Tay Sachs and Sandhoff diseases, are caused by β‐Hexosaminidase (HEXB) enzyme deficiency, resulting in ganglioside (GM2) accumulation and neuronal loss. The precise sequence of cellular events preceding, and leading to, neuropathology remains unclear, but likely involves inflammation and lysosomal accumulation of GM2 in multiple cell types. We aimed to determine the consequences of Hexb activity loss for different brain cell types using zebrafish. Hexb deficient zebrafish (hexb−/−) showed lysosomal abnormalities already early in development both in radial glia, which are the neuronal and glial progenitors, and in microglia. Additionally, at 5 days postfertilization, hexb−/− zebrafish showed reduced locomotor activity. Although specific oligosaccharides accumulate in the adult brain, hexb−/−) zebrafish are viable and apparently resistant to Hexb deficiency. In all, we identified cellular consequences of loss of Hexb enzyme activity during embryonic brain development, showing early effects on glia, which possibly underlie the behavioral aberrations. Hereby, we identified clues into the contribution of non‐neuronal lysosomal abnormalities in LSDs affecting the brain and provide a tool to further study what underlies the relative resistance to Hexb deficiency in vivo.

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Section: Resultsmentioning

confidence: 99%

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Kuil

Martí

Mascaro

et al. 2019

Glia

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“…While defective removal of dead phagocytes is assumed to be detrimental in other conditions such as atherosclerosis (Moore & Tabas, 2011), its reasons and significance in this disease await further clarification. In a mutant zebrafish model leading to lysosomal dysfunction, an increased volume of vacuolated lysosomes as found in MLD phagocytes had a negative impact on cell motility and clearance function (Berg et al, 2016;Shen, Sidik, & Talbot, 2016).…”

Section: Discussionmentioning

confidence: 99%

Microglia damage precedes major myelin breakdown in X‐linked adrenoleukodystrophy and metachromatic leukodystrophy

Bergner

Meer

Winkler

et al. 2019

Glia

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X‐linked adrenoleukodystrophy (X‐ALD) and metachromatic leukodystrophy (MLD) are two relatively common examples of hereditary demyelinating diseases caused by a dysfunction of peroxisomal or lysosomal lipid degradation. In both conditions, accumulation of nondegraded lipids leads to the destruction of cerebral white matter. Because of their high lipid content, oligodendrocytes are considered key to the pathophysiology of these leukodystrophies. However, the response to allogeneic stem cell transplantation points to the relevance of cells related to the hematopoietic lineage. In the present study, we aimed to better characterize the pathogenetic role of microglia in the above‐mentioned diseases. Applying recently established microglia markers to human autopsy cases of X‐ALD and MLD we were able to delineate distinct lesion stages in evolving demyelinating lesions. The immune‐phenotype of microglia was altered already early in lesion evolution, and microglia loss preceded full‐blown myelin degeneration both in X‐ALD and MLD. DNA fragmentation indicating phagocyte death was observed in areas showing microglia loss. The morphology and dynamics of phagocyte decay differed between the diseases and between lesion stages, hinting at distinct pathways of programmed cell death. In summary, the present study shows an early and severe damage to microglia in the pathogenesis of X‐ALD and MLD. This hints at a central pathophysiologic role of these cells in the diseases and provides evidence for an ongoing transfer of toxic substrates primarily enriched in myelinating cells to microglia.

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“…The optical transparency of the zebrafish larva, combined with the ease of genetic and pharmacological manipulation, make it an ideal model for in vivo imaging studies. Based on these advantages, several elegant studies have addressed microglial functions using the zebrafish as a model (Casano, Albert, & Peri, 2016;Herbomel, Thisse, & Thisse, 2001;Oosterhof et al, 2016;Peri & Nüsslein-Volhard, 2008;Rossi, Casano, Henke, Richter, & Peri, 2015;Shen, Sidik, & Talbot, 2016;Shiau, Monk, Joo, & Talbot, 2013;Sieger, Moritz, Ziegenhals, Prykhozhij, & Peri, 2012;Svahn et al, 2013;Xu, Wang, Wu, Jin, & Wen, 2016). In zebrafish, a subpopulation of primitive macrophages from the yolk sac colonize the brain early during development from 48 hr post fertilization (hpf) onwards.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling reveals a conserved microglia signature in larval zebrafish

Mazzolini

Clerc

Morisse

et al. 2019

Glia

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Microglia are the resident macrophages of the brain. Over the past decade, our understanding of the function of these cells has significantly improved. Microglia do not only play important roles in the healthy brain but are involved in almost every brain pathology. Gene expression profiling allowed to distinguish microglia from other macrophages and revealed that the full microglia signature can only be observed in vivo. Thus, animal models are irreplaceable to understand the function of these cells. One of the popular models to study microglia is the zebrafish larva. Due to their optical transparency and genetic accessibility, zebrafish larvae have been employed to understand a variety of microglia functions in the living brain. Here, we performed RNA sequencing of larval zebrafish microglia at different developmental time points: 3, 5, and 7 days post fertilization (dpf). Our analysis reveals that larval zebrafish microglia rapidly acquire the core microglia signature and many typical microglia genes are expressed from 3 dpf onwards. The majority of changes in gene expression happened between 3 and 5 dpf, suggesting that differentiation mainly takes place during these days. Furthermore, we compared the larval microglia transcriptome to published data sets of adult zebrafish microglia, mouse microglia, and human microglia. Larval microglia shared a significant number of expressed genes with their adult counterparts in zebrafish as well as with mouse and human microglia. In conclusion, our results show that larval zebrafish microglia mature rapidly and express the core microglia gene signature that seems to be conserved across species.

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The Rag-Ragulator Complex Regulates Lysosome Function and Phagocytic Flux in Microglia

Cited by 72 publications

References 69 publications

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Microglia damage precedes major myelin breakdown in X‐linked adrenoleukodystrophy and metachromatic leukodystrophy

Gene expression profiling reveals a conserved microglia signature in larval zebrafish

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