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. 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 have uncovered a complex transcriptional program, driven by an intricate network of transcription factors, epigenetic modifiers and non-coding RNAs, that coordinate this process. In contrast, much less is known about the translational control of myelination. Studies directed at exploring specific mechanisms regulating mRNA translation during myelination have barely been pursued, nor have their implications in myelin disorders been examined. The mission of MyeRIBO is to deconstruct the translational control of myelination and examine its implication in myelin disorders.
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. MyeRIBO is designed to discover the nature and diversity of the ribosome population in myelinating Schwann cells, and the mechanistic and functional role of these specialized ribosomes in regulating myelination. Building on these results, I will determine the contribution of ribosome heterogeneity in pathogenesis of myelin disorders.
Lesions to the myelin sheath result in devastating neurological disorders that include multiple sclerosis, diabetic neuropathy and Charcot-Marie-Tooth disease. Unfortunately, no therapeutical strategies are available for the vast majority of demyelinating neuropathies, as the precise molecular mechanisms of disease progression and functional failure remain poorly understood. 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.
