Molecular Membrane Neuroscience
Glucose-based lipid biology in nervous systems
In the last decades the importance of lipids in human health and disease has become increasingly evident. Perturbation of the lipid metabolic network is a key factor in the pathogenesis of many common diseases, such as coronary heart disease, metabolic syndrome, type 2 diabetes, cancer and neurodegenerative diseases. Taking into consideration that about halve of the human brain mass are lipids, the strong association of neurodegenerative diseases with alterations of the lipidome come at no surprise. In contrast to the completely sequenced human genome, however, the human lipidome is still poorly defined - in part, due to the enormous diversity of lipids and biosynthetic and metabolic pathways in brain. Additionally, the spatiotemporal dynamics of the lipid composition in cells, tissue and organs represent an enormous challenge, but offer an immense potential for predictive and preventative medicine as a source of novel biomarkers as well as drug targets for new therapies.
To address these shortcomings, my laboratory is focused on:
• Isolation and identification of novel lipids involved in brain pathogenesis
• Unraveling the biosynthesis, biological activity of novel lipid and its specific GPCR receptor
• Developing and optimizing advanced analytical techniques in brain lipid research
To achieve these aims, my laboratory is actively involved in collaboration with experts from Riken with medical background and synthetic chemistry. Due to our strong/long-term collaboration, we recently reported the first bioactive glycolipid, lyso-phosphatidylglucoside actively involved in guiding neuronal positioning in the journal Science (Guy, Nagatsuka et al., Science 2015).
Novel lipids in brain are generated at the crossroad of amino acid, glucose, and lipids (fatty acid, sterol).
Guy AT, Nagatsuka Y, Ooashi N, Inoue M, Nakata A, Greimel P, Inoue A, Nabetani T, Murayama A, Ohta K, Ito Y, Aoki J, Hirabayashi Y*, and Kamiguchi H* (*co-corresponding authors ): "NEURONAL DEVELOPMENT. Glycerophospholipid regulation of modality-specific sensory axon guidance in the spinal cord", Science, 349(6251):974-977, - Research Highlight in Nature Reviews Neuroscience (doi: 10.1038/nrn4035); Recommended in F1000 Prime (Highly Accessed) (2015)
Ishibashi Y, and Hirabayashi Y: "AMP-activated Protein Kinase Suppresses Biosynthesis of Glucosylceramide by Reducing Intracellular Sugar Nucleotides.", J Biol Chem 2015 Jul 17;290(29), 18245-60 (2015)
Kumagai A, Ando R, Miyatake H, Greimel P, Kobayashi T, Hirabayashi Y, Shimogori T, and Miyawaki A. : "Abilirubin-inducible fluorescent protein from eel muscle", Cell, 153(7), 1602-1611 (2013)
Kim YJ, Sano T, Nabetani T, Asano Y, and Hirabayashi Y: "GPRC5B Activates Obesity-Associated Inflammatory Signaling in Adipocytes.", Sci Signal, 5(251) (2012)
Kohyama-Koganeya A, Kim YJ, Miura M, and Hirabayashi Y: "A Drosophila orphan G protein-coupled receptor BOSS functions as a glucose-responding receptor: loss of boss causes abnormal energy metabolism.", Proc Natl Acad Sci U S A, 105(40), 15328-33 (2008)
Nagatsuka Y, Hara-Yokoyama M, Kasama T, Takekoshi M, Maeda F, Ihara S, Fujiwara S, Ohshima E, Ishii K, Kobayashi T, Shimizu K, and Hirabayashi Y: "Carbohydrate-dependent signaling from the phosphatidylglucoside-based microdomain induces granulocytic differentiation of HL60 cells.", Proc Natl Acad Sci U S A, 100, 7454-7459 (2003)
Furuya S, Tabata T, Mitoma J, Yamada K, Yamasaki M, Makino A, Yamamoto T, Watanabe M, Kano M, and Hirabayashi Y.: "L-serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons.", Proc Natl Acad Sci U S A, 97, 11528-11533 (2000)
Kanamori A, Nakayama J, Fukuda MN, Stallcup WB, Sasaki K, Fukuda M, and Hirabayashi Y.: "Expression cloning and characterization of a cDNA encoding a novel membrane protein required for the formation of O-acetylated ganglioside: a putative acetyl-CoA transporter", Proc Natl Acad Sci U S A, 94, 2897-2902 (1997)
Ichikawa S, Sakiyama H, Suzuki G, Hidari KI, and Hirabayashi Y.: "Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis", Proc Natl Acad Sci U S A, 93, 4638-4643 (1996)
Ichikawa S, Nakajo N, Sakiyama H, and Hirabayashi Y.: "A mouse B16 melanoma mutant deficient in glycolipids", Proc Natl Acad Sci U S A , 91, 2703-2707 (1994)