Metabolic Control of Proliferation and Differentiation in Oligodendrocytes

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Project Summary Myelin is critical for proper brain function and its dysfunction, damage or inappropriate formation has been reported in a wide range of neurological and psychiatric disorders, thereby urging the discovery of new potential treatments. This fellowship addresses the role of metabolism, and more specifically of glucose-derived acetyl- CoA (AcCoA), in regulating developmental myelination. The experimental aims rest on the solid premise that AcCoA is an unstable compound which cannot freely diffuse from one compartment to the next. The overarching hypothesis is that AcCoA function is dependent on the subcellular localization of its synthetic enzyme ATP citrate lyase (ACLY) and on the levels of the specific AcCoA transporter to the endoplasmic reticulum, SLC33A1. Aim 1 uses loss- and gain-of-function approaches to test the hypothesis that high glucose levels during the first postnatal week favor nuclear localization of ACLY and in turn promote synthesis of AcCoA and its incorporation into histones, thereby resulting in the expression of genes that favor proliferation and the maintenance of the progenitor state. It also posits that the transient decline of glucose during the second postnatal week is responsible for decreased nuclear ACLY, decreased nuclear AcCoA thereby favoring histone deacetylation and the transition of OPC from proliferating to differentiating cells. The hypothesis will be tested using Acly loss- and gain-of-function approaches in vitro in cultured OPC as well as lineage specific ablation in mice. The genome wide distribution of select histone acetylation marks will be tested using chromatin immunoprecipitation. Aim 2 uses loss- and gain-of-function approaches to test the hypothesis that increased cytosolic AcCoA synthesis in differentiating OL, followed by its transport to the endoplasmic reticulum (via SLC33A1) is crucial for the synthesis of cholesterol and myelin lipids. This hypothesis is supported by the detection of increased myelin in mice with systemic overexpression of the Slc33a1 transgene. The subaims will address OL differentiation and myelin development by matrix assisted laser desorption/ionization (MALDI) imaging, and electron microscopy. The training plan incorporates learning of new skills, such as advanced methodology in epigenetics, bioinformatics, lentiviral transduction, optogenetics and the latest in mass spectrometry imaging technologies. In addition, several opportunities will be offered to encourage training in experimental design, data analysis, as well as improvements in written and oral scientific communication and opportunities to mentor undergraduate students. Professional development opportunities will be available and participation in local, national, and international conferences will allow networking. As tangible milestones, the work is expected to result in two high quality, first author manuscripts as a doctoral trainee, and grant the opportunity to obtain a competitive post-doctoral appointment, leading to a career in academic science. This fellowship aligns the applicant’s long-term goal of studying metabolic regulation of brain cells, with the public health mission of NIH and NINDS to foster academic scientists and steward advances in our understanding of brain development and disease.