Autophagy and lysosomal dysfunction in Tay Sachs disease are restored by mTOR modulation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE184906 | GEO | 2021/09/30
REPOSITORIES: GEO
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Project description:Treatment of monogenic disorders has historically relied on symptomatic management with limited ability to target primary molecular deficits. However, recent advances in gene therapy and related technologies aim to correct these underlying deficiencies, raising the possibility of disease management or even prevention for diseases that can be treated pre-symptomatically. Tay–Sachs disease (TSD) would be one such candidate, however very little is known about the presymptomatic stage of TSD. To better understand the effects of TSD on brain development, we evaluated the transcriptomes of human fetal brain samples with biallelic pathogenic variants in HEXA. We identified dramatic changes in the transcriptome, suggesting a perturbation of normal development. We also observed a shift in the expression of the sphingolipid metabolic pathway away from production of the HEXA substrate, GM2 ganglioside, presumptively to compensate for dysfunction of the enzyme. However, we do not observe transcriptomic signatures of end-stage disease, suggesting that developmental perturbations precede neurodegeneration. To our knowledge, this is the first report of the relationship between fetal disease pathology in juvenile onset TSD and the analysis of gene expression in fetal TSD tissues. This study highlights the need to better understand the “pre-symptomatic” stage of disease to set realistic expectations for patients receiving early therapeutic intervention.
2023-02-08 | GSE224860 | GEO
Project description:Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of b-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells with CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids but not the HEXB-corrected organoids accumulated GM2 ganglioside, and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses
2018-10-30 | GSE106311 | GEO
Project description:Sandhoff disease (SD) is a lysosomal storage disorder characterized by the absence of β-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We found the alterations in the thymus during the development of mild to severe progressive neurologic disease. To elucidate the molecular basis of thymic involution, we performed cDNA microarray analysis to identify the changes in gene expression that accompanied the involution of the thymus. 8018 probes were found to be relatively increased in the thymus of the Hexb-/- mice, an animal model for SD, compared with that of the Hexb+/- mice. On the other hand, the expression of 7604 probes was relatively decreased. The cohort of up-regulated sequences was dominated by genes that play a role in the immune response. In addition, some of these genes are expressed in macrophage lineages such as macrophage expressed gene 1, and colony stimulating factor 2 receptor beta 1. Th2 cytokines were mostly upregulated in the Hexb-/- mice, although Th1 cytokines did not show this increase. In addition, B cell related genes such as CD19, CXCL13 were increased, whereas the T cell-related genes were mostly decreased, in Hexb-/- mice compared with Hexb+/- mice.
2009-12-25 | GSE19641 | GEO
Project description:Sanfilippo syndrome type B (MPS III B) is an autosomal recessive, neurodegenerative disease of children, characterized by profound mental retardation and dementia. The primary cause is mutation in the NAGLU gene, resulting in deficiency of N-acetylglucosaminidase and lysosomal accumulation of heparan sulfate. In the mouse model of MPS III B, neurons and microglia display the characteristic vacuolation of lysosomal storage of undegraded substrate, but neurons in the medial entorhinal cortex (MEC) display accumulation of several additional substances. We used whole genome microarray analysis to examine differential gene expression in MEC neurons isolated by laser capture microdissection from Naglu -/- and Naglu +/- mice. Neurons from the lateral entorhinal cortex (LEC) were used as tissue controls. The highest increase in gene expression (6- to 7-fold between mutant and control) in MEC and LEC neurons was that of Lyzs, which encodes lysozyme, but accumulation of lysozyme protein was seen in MEC neurons only. Because of a report that lysozyme induced the formation of hyperphosphorylated tau (P-tau) in cultured neurons, we searched for P-tau by immunohistochemistry. P-tau was found in MEC of Naglu -/- mice, in the same neurons as lysozyme. In older mutant mice, it was also seen in the dentate gyrus, an area important for memory. Electron microscopy of dentate gyrus neurons showed cytoplasmic inclusions of paired helical filaments - P-tau aggregates characteristic of tauopathies, a group of age-related dementias that includes Alzheimer disease. Our findings indicate that the Sanfilippo syndrome type B should also be considered a tauopathy. Two-condition experiment, Naglu-/- (affected) vs. Naglu+/- (unaffected control) of neurons from two adjacent brain regions: medial entorhinal cortex (MEC) and lateral entorhinal cortex (LEC). Biological replicates: 3 MEC Naglu-/-, 3 MEC Naglu+/-, 3 LEC Naglu-/- and 3 LEC Naglu+/-. Comparisons were made between 3 pairs of mutant and control female littermates for MEC and LEC neurons with dye switch duplicates, for a total of 12 microarrays.
2009-04-22 | E-GEOD-15758 | biostudies-arrayexpress
Project description:Autophagy and lysosomal dysfunction in Tay Sachs disease are restored by mTOR modulation
| PRJNA767011 | ENA
Project description:CLN3 is a type II transmembrane protein localized in the late endosomal/lysosomal compartment. A deficiency of CLN3 leads to the development of a certain type of Neuronal Ceroid Lipofuscinosis, a neurodegenerative disorder of childhood caused by aggregation of undegraded material in the lysosomal compartment. Cultured, immortalized wild type and Cln3(Δex7/8) cerebellar granule cells were used in this project to determine the influence of Cln3 deficiency on the proteome of the lysosomal compartment. For this purpose, cells were labelled by stable amino acid labelling in cell culture and lysosomes were isolated by magnetic beads.
2019-05-13 | PXD004548 | Pride
Project description:Sanfilippo syndrome type B (MPS III B) is an autosomal recessive, neurodegenerative disease of children, characterized by profound mental retardation and dementia. The primary cause is mutation in the NAGLU gene, resulting in deficiency of N-acetylglucosaminidase and lysosomal accumulation of heparan sulfate. In the mouse model of MPS III B, neurons and microglia display the characteristic vacuolation of lysosomal storage of undegraded substrate, but neurons in the medial entorhinal cortex (MEC) display accumulation of several additional substances. We used whole genome microarray analysis to examine differential gene expression in MEC neurons isolated by laser capture microdissection from Naglu -/- and Naglu +/- mice. Neurons from the lateral entorhinal cortex (LEC) were used as tissue controls. The highest increase in gene expression (6- to 7-fold between mutant and control) in MEC and LEC neurons was that of Lyzs, which encodes lysozyme, but accumulation of lysozyme protein was seen in MEC neurons only. Because of a report that lysozyme induced the formation of hyperphosphorylated tau (P-tau) in cultured neurons, we searched for P-tau by immunohistochemistry. P-tau was found in MEC of Naglu -/- mice, in the same neurons as lysozyme. In older mutant mice, it was also seen in the dentate gyrus, an area important for memory. Electron microscopy of dentate gyrus neurons showed cytoplasmic inclusions of paired helical filaments - P-tau aggregates characteristic of tauopathies, a group of age-related dementias that includes Alzheimer disease. Our findings indicate that the Sanfilippo syndrome type B should also be considered a tauopathy.
2009-04-22 | GSE15758 | GEO
Project description:We recently discovered that human neutrophils express immunomodulatory glycoproteins carrying unusual and highly truncated paucimannosidic N-glycans (Man1-3GlcNAc2Fuc0-1), but their biosynthesis remains elusive. Guided by the well-characterised truncation pathway in invertebrates and plants in which the N-acetyl-β-D-hexosaminidase (Hex) isoenzymes catalyse paucimannosidic protein (PMP) formation, we here set out to test if the homologous human Hex α and β subunits encoded by HEXA and HEXB drive a similar truncation pathway in human neutrophils. To this end, we performed quantitative glycomics and glycoproteomics of several CRISPR-Cas9-edited Hex-disrupted neutrophil-like HL-60 mutants (HEXA-/- and HEXB-/-) and matching unedited cell lines. Hex disruption was validated using next-generation sequencing, ELISA, proteomics and Hex activity assays. Excitingly, all Hex-disrupted mutants displayed significantly reduced levels of paucimannosylation, particularly of Man2-3GlcNAc2Fuc1, relative to unedited HL-60 suggesting that both HEXA and HEXB contribute to PMP formation via a hitherto unexplored truncation pathway in neutrophils. Quantitative N-glycomics indeed demonstrated reduced utilisation of a putative non-canonical truncation pathway in favour of the canonical elongation pathway in all Hex-disrupted mutants relative to unedited controls. Quantitative glycoproteomics recapitulated the truncation-to-elongation switch in all Hex-deficient mutants and showed a pronounced switch for N-glycoproteins co-trafficking with Hex to the azurophilic granules of neutrophils such as myeloperoxidase. Finally, we supported the Hex-PMP relationship by documenting that primary neutrophils isolated from an early-onset Sandhoff disease patient (HEXB-/-) displayed dramatically reduced paucimannosylation relative to neutrophils from an age-matched unaffected donor. We conclude that both human Hex α and β mediate PMP formation via a putative non-canonical truncation pathway in neutrophils.
2023-03-11 | PXD027664 | Pride
Project description:Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment epithelium (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used a mouse model of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. In a liver-specific Hepc (Hamp) knockout murine model of systemic iron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy, and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes, and ceramides. The proteolytic enzyme cathepsin D had impaired maturation. A large proportion of lysosomes were galectin-3 positive, suggesting cytotoxic lysosomal membrane permeabilization. RNA sequencing was performed and did not show evidence of upregulation of CLEAR network genes, suggesting that the lysosomal accumulation was due to decreased lysosomal turnover and not increased lysosomal biogenesis. Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely owing to iron-induced lipid peroxides that can inhibit lysosomal enzymes.
2023-07-13 | GSE237309 | GEO
Project description:Over-expression of wild type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation. In this study we used DNA microarrays to identify 1499 transcripts that are temporally deregulated concomitant with inducible PrPC over-expression in the skeletal muscles of transgenic mice. Examination using microarrays revealed a transcriptional profile with both similarities and differences to previously investigated models of myopathies. Down-regulation of genes coding for the myofibrillar proteins MYH2, MYH6, MYH7, MYL2, MYL3 and up-regulation of lysosomal genes CTSS, CTSD, CTSZ, DPEP2, HEXA, HEXB and LAMP1 coincide with the observed myopathy and lysosome accumulation on over-expression of PrPC. Down-regulation of the MEF2C gene, a key regulatory transcriptional factor muscle development and remodeling of adult muscles in response to physiologic and pathologic signals, may contribute to the centrally placed nuclei in the skeletal muscles. Significantly, up-regulation of genes involved in p53 signaling and the induction of p53 protein, suggest a central role for this molecule in the myopathy. Several p53-regulated genes involved in cell cycle arrest (CDNK1A, GADD45a and GADD45b) and apoptosis (BAK1, PMAIP1, BBC3, and BAX) are induced. We suggest that PrPC over-expression in skeletal muscles, possibly in response to accumulation of a cytotoxic truncated form of PrP, causes a primary myopathy involving the induction of p53-dependent pathways.
2008-08-27 | GSE12576 | GEO