We study protein glycosylation in different biological contexts, including physiology, development, and disease. It has been long recognized that glycans play essential roles in animal organisms, while defects in glycosylation are associated with numerous diseases and abnormalities, from cancer to brain malformation and defects in neurophysiology. However, the complexity of glycosylation and limitations of in vivo approaches impede research in mammals. We are using advantages of Drosophila model, including its powerful arsenal of genetic and in vivo approaches, to elucidate pathomechanisms underlying human diseases caused by glycosylation defects.
Pathomechanisms of abnormal protein O-Mannosylation
Our projects are focused on the mechanisms of protein O-mannosylation (POM) in neural development. Defects in POM have been implicated in severe disorders, such as muscular dystrophy, and lissencephaly. Using Drosophila as a model system, we discovered that POM is essential for the wiring of sensory axons and the neural control of muscle contractions. This project opened new avenues of research on new POM substrates and their functions in the regulation of neural connectivity. We currently employ a combination of genetic and biochemical approaches to identify novel functional targets of POM in the nervous system and characterize new enzymes involved in the POM pathway.
R. Baker, N. Nakamura, I. Chandel, B. Howell, D. Lyalin, V. M. Panin, Protein O-mannosyltransferases affect sensory axon wiring and dynamic chirality of body posture in the Drosophila embryo. J. Neurosci. 38, 1850–1865 (2018).
Regulation of neural transmission by sialylation
We investigate the role of neural sialylation in the regulation of neural development, excitability and transmission. We identified and characterized several key sialylation enzymes in Drosophila, including Drosophila sialyltransferase (DSiaT) and CMP-sialic acid synthetase (CSAS). Genetic inactivation of the sialylation pathway in vivo unveiled prominent roles of sialylated N-glycans in the regulation of the nervous system. Sialylation mutants have significantly reduced life span, locomotor abnormalities, and temperature-sensitive paralysis phenotype. We found that sialylation affects synaptic growth and the function of voltage-gated channels. Our studies established a model system to elucidate how this prominent glycosylation pathway controls neural functions. We currently investigate the molecular and cellular mechanisms that underlie the sialylation-mediated control of neural functions during development and aging.
I. Chandel, R. Baker, N. Nakamura, V. Panin, Live imaging and analysis of muscle contractions in Drosophila embryo. J. Vis. Exp. 149 (2019).
To Academic Professional Track Faculty