Neural precursor cell cultures from GM2 gangliosidosis animal models recapitulate the biochemical and molecular hallmarks of the brain pathology

Martino, Sabata; Girolamo, Ilaria di; Cavazzin, Chiara; Tiribuzi, Roberto; Galli, Rossella; Rivaroli, A.; Valsecchi, Manuela; Sandhoff, Konrad; Sonnino, Sandro; Vescovi, Angelo L.; Gritti, Angela; Orlacchio, Aldo

doi:10.1111/j.1471-4159.2009.05919.x

Cited by 36 publications

(38 citation statements)

References 43 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, (i) novel technologies allow the development of high-tech devices that mimick the damaged organs [1,2]; (ii) gene therapy strategies allow the substitution of the defective gene with the corresponding healthy copy and re-establish the lost protein function [3,4]; (iii) finally stem cell transplantation allows the replacement of damaged cells and repairs the tissue/organ homeostasis [5,6,7]. …”

Section: Regenerative Medicinementioning

confidence: 99%

Mechanotransduction: Tuning Stem Cells Fate

D’Angelo

Tiribuzi

Armentano

et al. 2011

JFB

Self Cite

View full text Add to dashboard Cite

It is a general concern that the success of regenerative medicine-based applications is based on the ability to recapitulate the molecular events that allow stem cells to repair the damaged tissue/organ. To this end biomaterials are designed to display properties that, in a precise and physiological-like fashion, could drive stem cell fate both in vitro and in vivo. The rationale is that stem cells are highly sensitive to forces and that they may convert mechanical stimuli into a chemical response. In this review, we describe novelties on stem cells and biomaterials interactions with more focus on the implication of the mechanical stimulation named mechanotransduction.

show abstract

Section: Regenerative Medicinementioning

confidence: 99%

Mechanotransduction: Tuning Stem Cells Fate

D’Angelo

Tiribuzi

Armentano

et al. 2011

JFB

Self Cite

View full text Add to dashboard Cite

show abstract

“…In particular, it was reported [5]–[6] that mouse neurons are enriched in a lysosomal ganglioside sialidase activity that removes the terminal sialic acid from G M2 ganglioside converting it into glycolipid G A2 which is further degraded by HexB. Most recent study in embryonic and postnatal brains and cultured neural cells derived from Tay-Sachs and Sandhoff mouse models shows that alternative roots for the formation of G M3 ganglioside also exist in Hexb −/− cells but they do not sufficiently reduce G M2 storage [9].…”

Section: Introductionmentioning

confidence: 99%

Mice Doubly-Deficient in Lysosomal Hexosaminidase A and Neuraminidase 4 Show Epileptic Crises and Rapid Neuronal Loss

et al. 2010

View full text Add to dashboard Cite

Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts GM2 to GM3 ganglioside. Hexa−/− mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise GM2 ganglioside via a lysosomal sialidase into glycolipid GA2, which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4 −/−;Hexa −/−) show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa −/− or Neu4 −/− siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating GM2 ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa−/− mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa −/− mice.

show abstract

“…pGeXSTrH17 β-hexosaminidase digestion resulted in more than one product and the relative GU values are shown in order of highest abundancy discrepancy in extent of elevation was possibly due to the presence of a mouse-specific sialidase that provides a bypass mechanism by hydrolysing the sialic acid residue from GM2 to form GA2, which in β-hexosaminidase active mice can be degraded by HexB [21,26]. In neuronal precursor cell cultures from Sandhoff disease and related Tay-Sachs disease model mice, lysosomal sialidase has recently been shown to be active in converting GM2 to GA2 glycolipid [27]. Furthermore, Takahata et al showed by lectin histochemistry, that an α2,3-sialidase is present in the cell line used in this study [28] further explaining the GM2 equilibrium following SR1 treatment.…”

Section: Discussionmentioning

confidence: 97%

Lysosomal storage of oligosaccharide and glycosphingolipid in imino sugar treated cells

et al. 2010

View full text Add to dashboard Cite

Sandhoff and Tay-Sachs disease are autosomal recessive GM2 gangliosidoses where a deficiency of lysosomal beta-hexosaminidase results in storage of glycoconjugates. Imino sugar (2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol) inhibition of beta-hexosaminidase in murine RAW264.7 macrophage-like cells led to lysosomal storage of glycoconjugates that were characterised structurally using fluorescence labelling of the free or glycolipid-derived oligosaccharides followed by HPLC and mass spectrometry. Stored glycoconjugates were confirmed as containing non-reducing GlcNAc or GalNAc residues resulting from the incomplete degradation of N-linked glycoprotein oligosaccharide and glycolipids, respectively. When substrate reduction therapeutics N-butyl-deoxynojirimycin (NB-DNJ) or N-butyldeoxygalactonojirimycin (NB-DGJ) were applied to the storage phenotype cells, an increase in glucosylated and galactosylated oligosaccharide species was observed due to endoplasmic reticulum alpha-glucosidases and lysosomal beta-galactosidase inhibition, respectively. Hexosaminidase inhibition triggered a tightly regulated cytokine-mediated inflammatory response that was normalised using imino sugars NB-DNJ and NB-DGJ, which restored the GM2 ganglioside storage burden but failed to reduce the levels of GA2 glycolipid or glycoprotein-derived N-linked oligosaccharides. Using a chemically induced gangliosidosis phenotype that can be modulated with substrate lowering drugs, the critical role of GM2 ganglioside in the progression of inflammatory disease is also demonstrated.

show abstract

Neural precursor cell cultures from GM2 gangliosidosis animal models recapitulate the biochemical and molecular hallmarks of the brain pathology

Cited by 36 publications

References 43 publications

Mechanotransduction: Tuning Stem Cells Fate

Mechanotransduction: Tuning Stem Cells Fate

Mice Doubly-Deficient in Lysosomal Hexosaminidase A and Neuraminidase 4 Show Epileptic Crises and Rapid Neuronal Loss

Lysosomal storage of oligosaccharide and glycosphingolipid in imino sugar treated cells

Contact Info

Product

Resources

About