Neuronal Expression of GalNAc Transferase Is Sufficient to Prevent the Age-Related Neurodegenerative Phenotype of Complex Ganglioside-Deficient Mice

Yao, Denggao; McGonigal, Rhona; Barrie, Jennifer A.; Cappell, Joanna; Cunningham, Madeleine E.; Meehan, Gavin R.; Fewou, Simon Ngamli; Edgar, Julia M.; Rowan, Edward G.; Ohmi, Yuhsuke; Furukawa, Koichi; Brophy, Peter; Willison, Hugh J.

doi:10.1523/jneurosci.3996-13.2014

Cited by 44 publications

(63 citation statements)

References 62 publications

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“…The requirement for de novo -synthesized GD3 in apoptotic pathways is well-established (De Maria et al , 1997; De Maria et al , 1998; Melchiorri et al , 2002; Morales et al , 2004), as is the literature showing neuroprotective effects of exogenous GM1 and manipulations that enhance endogenous GM1; in contrast, neurodegeneration is exacerbated neurodegeneration in animals with reduced GM1 (Ariga et al , 2013; Bernardo et al , 2009; Dhanushkodi & McDonald, 2011; Hadaczek et al , 2015; Wu et al , 2012; Yao et al , 2014). Thus our first inclination is to attribute the neuroprotective effect of GD3S deletion to the lack of GD3 and/or increased GM1.…”

Section: Discussionmentioning

confidence: 99%

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

Akkhawattanangkul

Maiti

Xue

et al. 2017

Genes Brain and Behavior

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Parkinson’s disease is a debilitating neurodegenerative condition for which there is no cure. Converging evidence implicates gangliosides in the pathogenesis of several neurodegenerative diseases, suggesting a potential new class of therapeutic targets. We have shown that interventions that simultaneously increase the neuroprotective GM1 ganglioside and decrease the pro-apoptotic GD3 ganglioside—such as inhibition of GD3 synthase (GD3S) or administration of sialidase—are neuroprotective in vitro and in a number of preclinical models. In the present study we investigated the effects of GD3S deletion on parkinsonism induced by 1-Methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP was administered to GD3S−/− mice or controls using a subchronic regimen consisting of three series of low-dose injections (11 mg/kg/day x 5 days each, 3 weeks apart), and motor function was assessed after each. The typical battery of tests used to assess parkinsonism failed to detect deficits in MPTP-treated mice. More sensitive measures—such as the force-plate actimeter and treadmill gait parameters—detected subtle effects of MPTP, some of which were absent in mice lacking GD3S. In wild-type mice MPTP destroyed 53% of the tyrosine-hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc) and reduced striatal dopamine 60.7%. In contrast, lesion size was only 22.5% in GD3S−/− mice and striatal dopamine was reduced by 37.2%. Stereological counts of Nissl-positive SNc neurons that did not express TH suggest that neuroprotection was complete but TH expression was suppressed in some cells. These results demonstrate that inhibition of GD3S has neuroprotective properties in the MPTP model may warrant further investigation as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

Akkhawattanangkul

Maiti

Xue

et al. 2017

Genes Brain and Behavior

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“…Questions remain concerning the cellular bases for the various anatomic and behavioral deficits reported. Conditional null mice in St3gal gene isoforms will help resolve these questions, as they did in the case of B4galnt1 ‐null mice, in which neuronal‐specific transgenic expression of B4galnt1 in knockouts was sufficient to counter the deficits of animal‐wide knockout, whereas glial‐specific transgenic expression was not (58).…”

Section: Discussionmentioning

confidence: 99%

Sialylation regulates brain structure and function

et al. 2015

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Every cell expresses a molecularly diverse surface glycan coat (glycocalyx) comprising its interface with its cellular environment. In vertebrates, the terminal sugars of the glycocalyx are often sialic acids, 9-carbon backbone anionic sugars implicated in intermolecular and intercellular interactions. The vertebrate brain is particularly enriched in sialic acid-containing glycolipids termed gangliosides. Human congenital disorders of ganglioside biosynthesis result in paraplegia, epilepsy, and intellectual disability. To better understand sialoglycan functions in the nervous system, we studied brain anatomy, histology, biochemistry, and behavior in mice with engineered mutations in St3gal2 and St3gal3, sialyltransferase genes responsible for terminal sialylation of gangliosides and some glycoproteins. St3gal2/3 double-null mice displayed dysmyelination marked by a 40% reduction in major myelin proteins, 30% fewer myelinated axons, a 33% decrease in myelin thickness, and molecular disruptions at nodes of Ranvier.

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“…Some of the models suffer from non-neural phenotypes and lack of cell specific ablation in the brain. Recovery of function in B4galnt1 -null mice by transgenic expression of B4galnt1 separately in nerve cells or glial cells has been highly revealing, demonstrating that the neurodegenerative phenotype in these mice was due to loss of gangliosides specifically in nerve cells [109]. Similar advances can be anticipated when conditional and multiple ganglioside biosynthetic gene deletions are made in mice.…”

Section: Tools and Challenges In Ganglioside Researchmentioning

confidence: 97%

Gangliosides of the Vertebrate Nervous System

Schnaar

2016

Journal of Molecular Biology

166

143

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Gangliosides, sialylated glycosphingolipids found on all vertebrate cells and tissues, are major molecular determinants on the surfaces of vertebrate nerve cells. Comprised of a sialylated glycan attached to a ceramide lipid, the same four structures – GM1, GD1a, GD1b and GT1b – represent the vast majority (>90%) of gangliosides in the brains of all mammals and birds. Primarily found on the outer surface of the plasma membrane with their glycans facing outward, gangliosides associate laterally with each other, sphingomyelin, cholesterol, and select proteins in lipid rafts – dynamic functional subdomains of the plasma membrane. The functions of gangliosides in the human nervous system are revealed by congenital mutations in ganglioside biosynthetic genes. Mutations in ST3GAL5, which codes for an enzyme early in brain ganglioside biosynthesis, results in an early-onset seizure disorder with profound motor and cognitive decay, whereas mutations in B4GALNT1, a gene encoding a later step, result in hereditary spastic paraplegia accompanied by intellectual deficits. The molecular functions of brain gangliosides include regulation of receptors in the same membrane via lateral (cis) associations and regulation of cell-cell recognition by trans interaction with ganglioside binding proteins on apposing cells. Gangliosides also affect aggregation of Aβ (Alzheimer’s disease) and α-synuclein (Parkinson’s Disease). As analytical, biochemical and genetic tools advance, research on gangliosides promises to reveal mechanisms of molecular control related to nerve and glial cell differentiation, neuronal excitability, axon outgrowth after nervous system injury, and protein folding in neurodegenerative diseases.

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Neuronal Expression of GalNAc Transferase Is Sufficient to Prevent the Age-Related Neurodegenerative Phenotype of Complex Ganglioside-Deficient Mice

Cited by 44 publications

References 62 publications

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

Sialylation regulates brain structure and function

Gangliosides of the Vertebrate Nervous System

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