Molecular mechanisms of localised Myelin Basic Protein synthesis in oligodendrocytes

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The myelination of neuronal axons and resulting saltatory conduction of action potentials is a prerequisite for efficient information processing in the central nervous system. The damage or lack of myelin has dramatic implications for nervous system function which is exemplified by the disease multiple sclerosis (MS), one of the most common neurologic disorders of young adults. Oligodendrocytes produce myelin by synthesizing huge amounts of membrane surface area which they wrap around axonal segments and compact. Myelin Basic Protein (MBP) is an essential component of myelin and its absence results in an inability to form functional myelin. MBP mRNA is transported in RNA granules from the nucleus to the cell membrane where it is translated locally in response to axonal signals so that MBP and eventually myelin synthesis can be regulated in a temporal and spatial manner. We recently identified molecules which can stimulate MBP mRNA translation in response to axonal signals and which can repress MBP mRNA translation during transport. We could show that an inhibitory small RNA molecule (sncRNA715) is enriched in MS lesions which could explain why oligodendrocytes in these lesions fail to produce MBP protein and myelin. In the proposed projects we intend to obtain a more detailed insight into the molecular mechanisms controlling the transition from inhibition to initiation of MBP translation. The supported experiments will reveal how MBP mRNA is converted from a translationally inactive into a translationally active state at its cellular destination. We intend to investigate a potential role of the RNA modulating Argonaute proteins in this context and to identify new molecules (proteins and RNAs) controlling the localised synthesis of MBP. These studies are important to understand how MBP- and myelin synthesis is regulated and this basic knowledge will contribute to the development of novel therapeutic approaches for demyelinating diseases such as MS. Furthermore they will contribute towards a better understanding of cellular RNA biology.