The facts of the matter: decoding the molecular properties of brain white matter using cell-type-specific quantitative proteomics

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Abstract The brain is built from an elaborate network of interactions between neurons and non-neuronal glial cells. Glial cells play active and essential roles in brain development and function, and glial dysfunction is increasingly implicated in neurological disorders. However, we still have a surprisingly limited understanding of the basic biology of most glial cell types and the importance of glial cell crosstalk for proper brain function. This is particularly true in the brain white matter, which comprises half of the volume of the human brain and possesses the highest glia-to-neuron ratio of any brain region. In recent years, advances in single cell sequencing have enabled a detailed study of the molecular and functional properties of neurons and glia in gray matter brain regions. Unfortunately, substantial technical barriers currently impede our ability to study the brain white matter and white matter glial cells at the same level of detail. Thus, our understanding of the molecular and functional properties of white matter lags behind that of gray matter, presenting a significant barrier to our understanding of healthy brain development and function and our ability to treat neurological disorders. To overcome these technical and scientific barriers, my lab will combine proximity-based in vivo quantitative proteomics with novel viral tools to define the molecular landscape of the brain white matter with regional, temporal, cellular, and subcellular specificity. We will perform these experiments in the healthy mouse brain at different developmental time points, as well as in established disease models where brain pathology is largely driven by white matter dysfunction. Ultimately, we will apply this proteomic data to investigate specific molecular mechanisms of glia-neuron and glia-glia crosstalk in brain white matter during brain development and disease, with a particular focus on the interaction of two glial cell types: astrocytes and oligodendrocytes. These experiments will provide an unprecedented window into the molecular architecture of the brain white matter and address several critical gaps in our understanding of how half of the brain develops, functions, and is impacted by disease.