Complex Carbohydrate Research Center, The University of Georgia （Senior Research Scientist）
|世話人||神村 圭亮 主席研究員（神経回路形成プロジェクト）
新井 誠 統合失調症プロジェクトリーダー（統合失調症プロジェクト）
Complex glycans on glycoproteins and glycosphingolipids (GSLs) mediate intra- and intercellular recognition and signaling events that influence many biological functions. Aberrant glycosylation arises from altered expression of glycan-related enzymes such as glycosyltransferases and glycosidases. Changes in the levels of these enzymes impact the structural diversity of glycoprotein and GSL glycans. Even seemingly subtle changes in glycan structure can have significant functional consequences on glycoprotein or GSL function. Therefore, it is important to visualize a comprehensive view of total glycomic changes in response to altered expression of glycan-related enzymes. We have developed comprehensive and quantitative glycomic methods to profile complex glycans in a broad range of biological materials by mass spectrometry (MS). Our analytic approaches allow us to obtain multiple glycome profiles (N-linked, O-linked glycoprotein glycans, as well as GSL glycans, free oligosaccharides and lipid-linked oligosaccharide precursors). Our MS-based glycomic methods have produced a greater understanding of the biological consequences of altered glycosylation in human disorders. For example, we have been investigating a rare human disorder termed “Salt-and-Pepper” syndrome caused by a missense mutation in ST3GAL5, the sialyltransferase responsible for the synthesis of ganglioside GM3. Knockout of the enzyme in mouse generated a viable, fertile animal with relatively mild phenotypic consequences. In contrast, patients with a mutation in the ST3GAL5 gene exhibit a complex range of phenotypes including profound intellectual disability, failure to thrive, early lethality, seizures, and altered cutaneous pigmentation, leading to the name “Salt-and-Pepper” syndrome (S&PS). Thus, the value of the mouse is somewhat limited for investigating the impact of altered GM3 biosynthesis in humans. To understand the contribution of GM3 deficiency to the pathology of S&PS and, by extension, to gain greater insight into the normal function of complex gangliosides, we have investigated the cell lineage-specific consequences of altered glycosylation in S&PS using iPS technology. We have reported that deficiency of GM3 synthase alters glycosphingolipid (GSL) glycan and ceramide structural diversity, as well as modifying glycoprotein glycosylation, both of which may contribute to the pathophysiology of the disease. S&PS was identified in a single family in South Carolina. The S&PS mutation is allelelic to a GM3 synthase deficiency disorder identified in the Amish population, known as Amish Epilepsy Syndrome (AES). We have demonstrated that loss of function of ST3GAL5 in AES also results in complete loss of plasma ganglioside GM3 and other complex gangliosides. Two approaches for treating AES by restoring GM3 levels have been undertaken. For each of these, we have monitored plasma GSL levels by MS. We quantified GSLs for a cohort of AES patients treated by oral supplementation with milk gangliosides and for a single patient given an umbilical cord blood transplant. In addition, we have applied our methods to understand the pathophysiology of altered glycoprotein and glycolipid glycosylation in human neurodegenerative, developmental, and cognitive disorders in Anderson Fabry disease, Familial Alzheimer’s (FAD), Autism Spectrum Disorder (ASD), and X-linked intellectual disability (XLID), expands our search for other human disorders of glycosylation that impact neural function, and investigates pharmacologic approaches for modulating glycosylation.