Project description
Control of myelination and specialised ribosomes
Myelin is a lipid-based layer that surrounds nerve cell axons to insulate and increase the rate of electrical transduction along the axon. Myelin is formed by glial cells called oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Myelination involves expansion of the glial cell membrane, which is the result of an increase in protein and lipid synthesis rates. There is emerging evidence that ribosomes are not just passive molecular machines and are heterogeneous in composition, and that particular ribosomal components might play a regulatory role of preferential translation of specific mRNAs. The EU-funded MyeRIBO project will employ advanced electron microscopy, quantitative proteomics, genome-wide ribosome profiling and genetic mouse models to investigate translation control by specialised ribosomes as a novel mechanism of regulation of myelination by the glial cells. MyeRIBO could have profound impact for understanding neural development and myelin disorders.
Objective
The myelin sheath is essential for neuronal function and health: myelinating glial cells speed up propagation of axonal potentials, fuel the energetic demands and regulate the ionic environment of neurons. Lesions to the myelin sheath thus result in devastating neurological disorders that include multiple sclerosis, diabetic neuropathy and Charcot-Marie-Tooth disease. Myelination involves a striking expansion of the glial cell membrane that relies on an exceptional increase in protein and lipid synthesis rates. Decades of dedicated research has uncovered a complex transcriptional program that drives this process, whereas translational control mechanisms, on the other hand, have received little attention. There is emerging evidence, enabled by modern techniques, that ribosomes, typically viewed as invariant, passive molecular machines, may instead be heterogeneous in composition, with particular ribosomal components having a ‘specialized’ regulatory capacity for preferential translation of specific mRNAs. In MyeRIBO, I propose that translation control by specialized ribosomes is a novel layer of regulation that shapes the proteome of the myelinating glial cell. I will exploit advances in cryo-EM and quantitative proteomics analyses to discover the nature and diversity of ribosomes in myelinating cells, employ genome-wide ribosome profiling to obtain mechanistic insights into selective mRNA translation by heterogeneous ribosomes, and generate genetic mouse models to determine the functional consequences of this specialization for myelination in vivo. Notably, I will study the implication of this mechanism in pathogenesis of injury-induced demyelination and diabetic neuropathy, and evaluate the targeting of specialized ribosomal components as a preclinical strategy. MyeRIBO will push further the boundaries of our current understanding of the molecular control of myelination, which could have a profound impact for understanding neural development and myelin disorders.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesclinical medicineendocrinologydiabetes
- medical and health sciencesbasic medicineneurologymultiple sclerosis
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- engineering and technologyenvironmental engineeringenergy and fuels
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
15782 Santiago De Compostela
Spain