Unconventional N-Glycosylation and Diversification of Neuronal Ion Channel Properties – GLYCOSTAB

Neuronal development and synaptic transmission require the continuous production of secreted trophic factors and transmembrane proteins such as adhesion proteins, neurotransmitter receptors, ion-channels, and thus heavily rely on the secretory machinery: the endoplasmic reticulum (ER) and the Golgi apparatus (GA), where these proteins are synthesized and, in most cases, chemically modified by addition of complex sugars during N-glycosylation.

N-glycosylation is the second most frequent protein post-translational modification after phosphorylation and regulates every aspect of the biology of membrane proteins, and in particular their trafficking to the cell-surface and their stability. Congenital N-glycosylation defects, especially in brain, result in usually lethal developmental disorders, while milder forms lead to mental retardation. Despite a likely central role in neurons, strikingly little is known on the N-glycosylation of neuronal proteins.

My recent work shows that, as a result of unconventional secretory processing, many surface-expressed neurotransmitter receptors, voltage-gated ion channels and synaptic adhesion proteins display glycosylation profiles that are typically associated with immature proteins before their export to the cell surface. This so-called core-glycosylation is associated with a faster protein turnover and is regulated by synaptic activity, unraveling a novel mechanism controlling the electrical and chemical sensing properties of the neuronal membrane.

My specific aims for the short and midterm future are: 1) to assess the contribution of unconventional N-glycans to dendritic growth and synaptic signaling; and 2) to determine the impact of local protein synthesis on the N-glycosylation, surface expression, stability and regulability of synaptic proteins during synaptic plasticity.