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Local Processing of Dendritically Synthesized Membrane Proteins

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Local synthesis, atypical N-glycosylation and turnover of neuronal surface proteins

Local protein synthesis is a particularly efficient means to locally control the molecular composition of targeted cellular compartments. New data indicate that local protein synthesis in neuronal dendrites may enable neurons to control the glycosylation status and hence the stability and function of key surface proteins.

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Neuronal development and synaptic transmission require the continuous production of secreted trophic factors and transmembrane proteins, for example neurotransmitter receptors, adhesion molecules and ion-channels, and thus heavily rely on the secretory machinery: the endoplasmic reticulum and the Golgi apparatus, 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. Yet and despite a likely central role in neurons, strikingly little is known on the N-glycosylation of neuronal proteins. The results of the EU-funded DENDRITIC PROCESSING (Local processing of dendritically synthesized membrane proteins) project indicate that the spatial segregation of membrane protein synthesis and processing in the soma versus dendrites allows neurons to exploit multiple secretory pathways to diversify the properties (e.g. stability, desensitization) of surface membrane proteins. More specifically, researchers found that, as a result of unconventional secretory processing, hundreds of key 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 core-glycosylation is associated with a faster protein turnover and is regulated by synaptic activity, unravelling a novel mechanism controlling the electrical and chemical sensing properties of the neuronal membrane. Another important milestone of the project was the development of a new transgenic mouse line for genetic targeting of protein metabolites in the mammalian brain. This model enables the conditional expression of an enzyme methionyl tRNA synthetase L274G to incorporate non-canonical amino acids as 'tags' in the proteins made by specific cells for subsequent isolation or visualization. Glycosylation is a critical stage in the processing and turnover of membrane and secreted molecules in the cell. It is not surprising that N-glycosylation defects in the brain result in severe and often lethal developmental disorders. The concept of locally regulated glycosylation and protein turnover is important for better understanding of such disorders and their diagnosis.


Protein turnover, neuronal, membrane protein, dendrites, glycosylation

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