g(m2)-ganglioside and Nerve-Degeneration

GM2 ganglioside in the brain increased during ethanol-induced acute apoptotic neurodegeneration in 7-day-old mice. A small but a significant increase observed 2 h after ethanol exposure was followed by a marked increase around 24 h. Subcellular fractionation of the brain 24 h after ethanol treatment indicated that GM2 increased in synaptic and non-synaptic mitochondrial fractions as well as in a lysosome-enriched fraction characteristic to the ethanol-exposed brain. Immunohistochemical staining of GM2 in the ethanol-treated brain showed strong punctate staining mainly in activated microglia, in which it partially overlapped with staining for LAMP1, a late endosomal/lysosomal marker. Also, there was weaker neuronal staining, which partially co-localized with complex IV, a mitochondrial marker, and was augmented in cleaved caspase 3-positive neurons. In contrast, the control brain showed only faint and diffuse GM2 staining in neurons. Incubation of isolated brain mitochondria with GM2 in vitro induced cytochrome c release in a manner similar to that of GD3 ganglioside. Because ethanol is known to trigger mitochondria-mediated apoptosis with cytochrome c release and caspase 3 activation in the 7-day-old mouse brain, the GM2 elevation in mitochondria may be relevant to neuroapoptosis. Subsequently, activated microglia accumulated GM2, indicating a close relationship between GM2 and ethanol-induced neurodegeneration.

Topics: Animals; Apoptosis; Blotting, Western; Brain; Brain Chemistry; Caspase 3; Central Nervous System Depressants; Cytochromes c; Endosomes; Enzyme Activation; Ethanol; G(M2) Ganglioside; Immunohistochemistry; Lysosomes; Mice; Mice, Inbred C57BL; Microscopy, Electron; Mitochondria; Nerve Degeneration; Subcellular Fractions

Myeloid-derived immune cells, including microglia, macrophages and monocytes, have been previously implicated in neurodegeneration. We investigated the role of infiltrating peripheral blood mononuclear cells (PBMC) in neuroinflammation and neurodegeneration in the HexB-/- mouse model of Sandhoff disease. Ablation of the chemokine receptor CCR2 in the HexB-/- mouse resulted in significant inhibition of PBMC infiltration into the brain, decrease in TNFalpha and MHC-II mRNA abundance and retardation in clinical disease development. There was no change in the level of GM2 storage and pro-apoptotic activity or astrocyte activation in HexB-/-; Ccr2-/- double knockout mice, which eventually succumbed secondary to GM2 gangliosidosis.

Topics: Animals; Apoptosis; Disease Models, Animal; Encephalitis; Female; G(M2) Ganglioside; Hexosaminidase B; Leukocytes, Mononuclear; Male; Mice; Mice, Knockout; Microglia; Nerve Degeneration; Receptors, CCR2; Sandhoff Disease

Sandhoff disease involves the CNS accumulation of ganglioside GM2 and asialo-GM2 (GA2) due to inherited defects in the beta-subunit gene of beta-hexosaminidase A and B (Hexb gene). Accumulation of these glycosphingolipids (GSLs) produces progressive neurodegeneration, ultimately leading to death. Substrate reduction therapy (SRT) aims to decrease the rate of glycosphingolipid (GSL) biosynthesis to compensate for the impaired rate of catabolism. The imino sugar, N-butyldeoxygalactonojirimycin (NB-DGJ) inhibits the first committed step in GSL biosynthesis. NB-DGJ treatment, administered from postnatal day 2 (p-2) to p-5 (600 mg/kg/day)), significantly reduced total brain ganglioside and GM2 content in the Sandhoff disease (Hexb(-/-)) mice, but did not reduce the content of GA2. We also found that NB-DGJ treatment caused a slight, but significant elevation in brain sialidase activity. The drug had no adverse effects on viability, body weight, brain weight, or brain water content in the mice. No significant alterations in neutral lipids or acidic phospholipids were observed in the NB-DGJ-treated Hexb(-/-) mice. Our results show that NB-DGJ is effective in reducing total brain ganglioside and GM2 content at early neonatal ages.

Topics: 1-Deoxynojirimycin; Animals; Animals, Newborn; beta-Hexosaminidase alpha Chain; Brain; Brain Chemistry; Disease Models, Animal; Down-Regulation; G(M2) Ganglioside; Gangliosides; Glycosphingolipids; Mice; Mice, Knockout; Nerve Degeneration; Neuraminidase; Sandhoff Disease; Treatment Outcome

To investigate the effects of lysosomal storage on the morphologic appearance and the neurite outgrowth capability of the retina in a mouse model of G(M2) gangliosidosis (Sandhoff disease).. Histopathologic appearances of retinas in Sandhoff (SD) mice at 3 and 4 months of age were examined by light and electron microscopy. Retinas of SD mice and wild-type (WT) mice at 1, 2, and 4 months of age were cultured in collagen gel in the presence or absence of brain-derived neurotrophic factor (BDNF), and neurite outgrowth was examined.. Morphologic studies revealed accumulation of G(M2) ganglioside in the retinal ganglion cells of SD mice in a time-dependent manner. The number of neurites from the retinal explants after 7 and 10 days in culture were significantly lower in 2- and 4-month-old SD mice than in the age-matched WT mice. The application of BDNF significantly improved neurite outgrowth from the retina in both SD and WT mice at 2 months of age. At 4 months of age, BDNF was much less effective at stimulating neurite outgrowth in the retina of SD mice than in retina of WT mice.. These results indicate that lysosomal storage of G(M2) ganglioside impairs the capability of neurite outgrowth in retinal ganglion cells in culture and that BDNF is effective at diminishing this impairment during the early stage of the disease.

Topics: Animals; beta-N-Acetylhexosaminidases; Brain-Derived Neurotrophic Factor; Disease Models, Animal; G(M2) Ganglioside; Mice; Mice, Knockout; Nerve Degeneration; Neurites; Organ Culture Techniques; Retinal Diseases; Retinal Ganglion Cells; Sandhoff Disease; Time Factors

This paper describes an 11-month-old male who died of Sandhoff disease. Diagnosis was based on detection of cherry red spots and total deficiency of hexosaminidase A and B activities. Sections of the brain revealed swollen neuronal cells and their degeneration and disappearance, leaving a distorted cortical architecture. Ultrastructurally, numerous inclusions showing concentric lamellar or stacked lamellar profiles were found in ballooned neuronal cells, astrocytes and histiocytes. The parafoveal retina in the region of the cherry red spot contained ballooned ganglion and amacrine cells filled with PAS and LFB positive granules. Electron microscopically, these cells showed a greater accumulation of inclusions with stacked lamellar profiles, than the concentric lamellar ones, of classically membranous cytoplasmic bodies (MCB). Hepatocytes and Kupffer cells and epithelial cells of renal glomeruli contained pleomorphic inclusions. Biochemical analysis by thin-layer chromatography of lipid extracts from the cerebral cortex showed a marked increment of the GM2 fraction, without an increase in globoside.

Topics: Brain; Cerebral Cortex; Chromatography, Thin Layer; Extracellular Space; G(M2) Ganglioside; Gangliosides; Humans; Inclusion Bodies; Infant; Intracellular Membranes; Male; Nerve Degeneration; Neurons; Sandhoff Disease

Gangliosidoses are very rare neurological diseases based on specific enzyme defects. They constitute models for the disruption of specific metabolic pathways and cellular functions with the ultimate consequence of manifest clinical symptoms. The investigation of the various steps involved in the generation of a given syndrome can therefore lead to a more profound understanding of the cell biology of the nervous system. In the present synopsis we try to briefly summarize some aspects of the present knowledge of pathophysiological mechanisms in GM1- and GM2-gangliosidoses.

Topics: beta-Galactosidase; beta-N-Acetylhexosaminidases; Brain; Child; G(M1) Ganglioside; G(M2) Activator Protein; G(M2) Ganglioside; Gangliosides; Gangliosidoses; Glycoproteins; Hexosaminidases; Humans; Lysosomes; Nerve Degeneration; Protein Deficiency; Proteins; Saposins; Sphingolipid Activator Proteins; Synaptic Transmission

Topics: Axons; Cell Line; Child; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Gangliosidoses; Humans; Motor Endplate; Motor Neurons; Muscles; Nerve Degeneration; Nerve Growth Factors; Nerve Regeneration; Neuromuscular Junction; Neurons; Peripheral Nerves; Synaptic Transmission

GM1 and GM2 gangliosidoses are progressive neurodegenerative diseases which accumulate intralysosomal gangliosides--and to a lesser extent oligosaccharides--chiefly in the central and peripheral nervous system owing to deficiencies of beta-galactosidase and hexosaminidases A or/and B, respectively. This intralysosomal "storage" in neuronal pericarya and their processes, and subsequent loss of such nerve cells provide the background for clinical symptoms of the central nervous system and the retina, while involvement of the peripheral nervous system and the visceral organs largely remains free of clinical findings. The morphological involvement of the latter organs is widespread though varying, thus allowing morphological investigations of lymphocytes, skin, or rectum for morphological diagnosis and as a screening procedure.

Topics: Astrocytes; Brain; Child; Dendrites; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Gangliosidoses; Humans; Inclusion Bodies; Lysosomes; Microscopy, Electron; Nerve Degeneration; Neurons; Peripheral Nerves; Sandhoff Disease; Spinal Cord; Synaptic Membranes; Tay-Sachs Disease; Vacuoles