Post-translational modification of brain proteins with O-linked N-acetyl-D-glucosamine

Yuliya Skorobogatko

doi:10.17918/00009737

This work contributes to understanding how post-translational modifications of proteins modulate synaptic function. Modification of synaptic proteins with the regulatory intracellular carbohydrate 0-linked N-acetylglucosamine (0-G1cNAc) is the focus of this study, which resulted in mapping of the first 0-G1cNAc sites on human brain proteins and established that modification of the synaptic protein, synapsin I, with 0-G1cNAc modulates synaptic plasticity (a property of neurons to modulate the strength of communication between synapses which is indispensible for learning and memory). Previously we found that pharmacological elevation of 0-G1cNAc in mouse brain facilitates synaptic plasticity. This facilitation is in part due to a presynaptic mechanism. One of the important presynaptic mechanisms of synaptic plasticity is generation and mobilization of a so called "reserve pool" of synaptic vesicles, which is used in addition to a "readily releasable pool" to maintain neurotransmitter release during times of high neuronal activity. Synapsin I, which is extensively modified by 0-G1cNAc, is a key synaptic vesicle binding protein that regulates the size and release of the reserve pool. Disruption of synapsin I function compromises the reserve pool of synaptic vesicles, leading to epilepsy and memory deficits. We addressed the role of synapsin I 0- GIcNAcylation in synaptic plasticity using a combination of biochemical tools, molecular biology, and imaging in primary hippocampal neurons. Based on our findings we propose a model where O-GlcNAcylation of synapsin I disrupts its association with synaptic vesicles and promotes trafficking of synaptic vesicles from the reserve pool to the readily releasable pool, thus facilitating synaptic plasticity. A single 0-GleNAc site, Thr87 which is crucial for regulating synapsin I, is located within the amphipathic lipid-packing sensor (ALPS) motif, which is responsible for preferential association of synapsin I with synaptic vesicles vs. the cell membrane. Thus, Thr87 0-GIcNAcylation decreases the affinity of synapsin I to synaptic vesicles likely through the disruption of the ALPS motif function. Since we found that synapsin 0-GleNAcylation is increased during synapse maturation, we propose that the regulation of synapsin I by 0-GIcNAc is important during synaptogenesis. Meanwhile the regulation of synapsin I O-GlcNAcylation during neurotransmission remains to be investigated.

Post-translational modification of brain proteins with O-linked N-acetyl-D-glucosamine

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Post-translational modification of brain proteins with O-linked N-acetyl-D-glucosamine

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