Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB

Ohmi, Kazuhiro; Greenberg, David; Rajavel, Kavitha S.; Ryazantsev, Sergey; Li, Hong Hua; Neufeld, Elizabeth F.

doi:10.1073/pnas.252784899

Cited by 377 publications

(341 citation statements)

References 37 publications

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“…Trehalose treatment significantly reduced the number of large autophagic vacuoles (indicated with arrows in magnified images) in the cortex (0.2 ± 0.11; 0.9 ± 0.12 AV/cell; n = 20 cells; P = 0.0002) and cerebellum (0.8 ± 0.2; 4.7 ± 0.94 AV/cell; n = 10 cells; P = 0.002) (Figure 5(a–b)). Large inclusions within microglia in the cortex were also seen in naglu –/ – mice (Figure 5(c)), as previously reported [48]. These inclusions were not found in trehalose-treated naglu –/ – mice (Figure 5(c)), which might be due to an increase in autophagic flux.…”

Section: Resultssupporting

confidence: 85%

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu–/ – mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs.Abbreviations: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKCα: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus

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Section: Resultssupporting

confidence: 85%

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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“…4B). The presence of GM3 ganglioside in microglia had been observed previously in the MPS III B mice at the level of light microscopy [35].…”

Section: Gm3 Ganglioside At the Em Levelsupporting

confidence: 68%

Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B

Ryazantsev

Zhao

et al. 2007

Molecular Genetics and Metabolism

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The neurodegenerative disease MPS III B (Sanfilippo syndrome type B) is caused by mutations in the gene encoding the lysosomal enzyme α-N-acetylglucosaminidase, with a resulting block in heparan sulfate degradation. A mouse model with disruption of the Naglu gene allows detailed study of brain pathology. In contrast to somatic cells, which accumulate primarily heparan sulfate, neurons accumulate a number of apparently unrelated metabolites, including subunit c of mitochondrial ATP synthase (SCMAS). SCMAS accumulated from 1 month of age, primarily in the medial entorhinal cortex and layer V of the somatosensory cortex. Its accumulation was not due to the absence of specific proteases. Light microscopy of brain sections of 6 months-old mice showed SCMAS to accumulate in the same areas as glycosaminoglycan and unesterified cholesterol, in the same cells as ubiquitin and GM3 ganglioside, and in the same organelles as Lamp 1 and Lamp 2. Cryo-immuno electron microscopy showed SCMAS to be present in Lamp positive vesicles bounded by a single membrane (lysosomes), in fingerprint-like layered arrays. GM3 ganglioside was found in the same lysosomes, but was not associated with the SCMAS arrays. GM3 ganglioside was also seen in lysosomes of microglia, suggesting phagocytosis of neuronal membranes. Samples used for cryo-EM and further processed by standard EM procedures (osmium tetroxide fixation and plastic embedding) showed the disappearance of the SCMAS fingerprint arrays and appearance in the same location of "zebra bodies", well known but little understood inclusions in the brain of patients with mucopolysaccharidoses.

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“…4a) as well as in brain, lung, synovium, heart valves, aorta, and trachea (data not shown) from Sumf1 Ϫ/Ϫ mice, indicating significant storage that is likely due to the simultaneous deficiency of several lysosomal sulfatases. Immunohistochemical analysis using MOMA-2 [monoclonal antibody against macrophages (17)] antibody revealed a massive presence of macrophages in all tissues examined from Sumf1 Ϫ/Ϫ mice as early as at postnatal day (P)5, indicating the presence of a systemic inflammatory process (Fig. 4b).…”

Section: Resultsmentioning

confidence: 99%

Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency

Settembre

Annunziata

Spampanato

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Sulfatases are involved in several biological functions such as degradation of macromolecules in the lysosomes. In patients with multiple sulfatase deficiency, mutations in the SUMF1 gene cause a reduction of sulfatase activities because of a posttranslational modification defect. We have generated a mouse line carrying a null mutation in the Sumf1 gene. Sulfatase activities are completely absent in Sumf1 ؊/؊ mice, indicating that Sumf1 is indispensable for sulfatase activation and that mammals, differently from bacteria, have a single sulfatase modification system. Similarly to multiple sulfatase deficiency patients, Sumf1 ؊/؊ mice display frequent early mortality, congenital growth retardation, skeletal abnormalities, and neurological defects. All examined tissues showed progressive cell vacuolization and significant lysosomal storage of glycosaminoglycans. Sumf1 ؊/؊ mice showed a generalized inflammatory process characterized by a massive presence of highly vacuolated macrophages, which are the main site of lysosomal storage. Activated microglia were detected in the cerebellum and brain cortex associated with remarkable astroglyosis and neuronal cell loss. Between 4 and 6 months of age, we detected a strong increase in the expression levels of inflammatory cytokines and of apoptotic markers in both the CNS and liver, demonstrating that inflammation and apoptosis occur at the late stage of disease and suggesting that they play an important role in both the systemic and CNS phenotypes observed in lysosomal disorders. This mouse model, in which the function of an entire protein family has been silenced, offers a unique opportunity to study sulfatase function and the mechanisms underlying lysosomal storage diseases.apoptosis ͉ macrophages ͉ sulfatase modifying factor 1

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Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB

Cited by 377 publications

References 37 publications

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B

Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency

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