Dissertations, Theses, and Capstone Projects

Date of Degree


Document Type


Degree Name





Patrizia Casaccia

Committee Members

Carmen Melendez-Vasquez

Andreas Kottmann

Luigi Puglielli

Xinyin Jiang

Subject Categories

Biology | Cell and Developmental Biology | Genetics and Genomics | Neuroscience and Neurobiology


oligodendrocyte proliferation metabolism epigenetics development differentiation


Oligodendrocytes (OLs) are specialized cells whose membrane extension, called myelin, wraps the axons providing insulation, trophic and metabolic support, and is essential for proper functioning of the central nervous system. Inappropriate myelin formation, damage or dysfunction of oligodendrocytes has been identified in several neurological disorders and often precedes the loss of neuronal cells. OLs derive from proliferating oligodendrocyte progenitor cells (OPCs), which exit from the cell cycle and undergo a series of transcriptional and epigenetic events, including histone post-translational modifications, resulting in morphological and functional changes. Our lab previously identified elevated levels of histone acetylation in proliferating OPCs during the first postnatal week of development. Histone acetylation is a mark of transcriptional activation, and it is catalyzed by nuclear lysine acetyltransferases (KATs), which use nuclear acetyl-Coenzyme A to acetylate lysine residues on histone tails and other proteins. Removal of acetyl groups from specific histone lysine residues, mediated by histone deacetylases (HDACs), is necessary for the repression of genes preventing the transition of OPCs to OLs and essential for the early stages of developmental myelination, and adult remyelination. Acetyl-CoA is therefore a metabolite that appears to be critical to the differentiation of OPCs. The central hypothesis tested by this doctoral thesis is that changes to acetyl-CoA bioavailability follow the metabolic fluctuations in glucose, with decreased levels occurring during a temporal window corresponding to the onset of developmental myelination. We also posit that, while glucose as bioenergetic fuel can be replaced by ketone bodies, its ability to generate acetyl-CoA from citrate cannot be replaced. Thus, glucose levels in the brain have the unique role of modulating the levels of nuclear acetyl-CoA and the activity of acetyltransferases that are responsible for the acetylation of histones and other substrates and in turn influence the decision of OPCs to either proliferate or differentiate into OLs. The generation of acetyl-CoA from glucose-derived citrate is mediated by the extra-mitochondrial enzyme ATP Citrate LYase (ACLY). In the nucleus, ACLY is responsible for the production of acetyl-CoA, which serves as a substrate for protein acetylation and signals OPCs to increase expression of cell cycle genes and proliferate. When glucose is low, as I detect during the critical temporal window of development, or ACLY activity is low, due to pharmacological inhibition or cell-specific genetic ablation, the expression of several genes regulating proliferation is decreased. In low glucose conditions, cells survive by utilizing ketone bodies as alternative fuel, and yet, fewer OPCs enter the cell cycle, the levels of histone H3K9 acetylation decrease and transcripts regulating proliferation are also decreased, while early differentiation markers are upregulated. Similar events occur when ACLY catalytic activity is pharmacologically inhibited, even if the OPCs are maintained in high glucose conditions. In vivo, a progenitor specific Acly knockout mouse line similarly shows decreased histone H3K9 acetylation and fewer proliferating OPCs in developing white matter tracts. Single cell transcriptomics of Acly-null OPCs further suggested an arrest of progenitors in the G2 phase of the cell cycle. Overall, my results support the hypothesis that ACLY-dependent acetyl-CoA production from glucose is an important determinant in the decision of progenitors to proliferate and that reduced glucose availability observed during early brain development may serve as a signal to OPCs to undergo cell cycle exit and subsequent differentiation. Importantly, in Acly knockout mice, I also detected delayed myelination. As acetyl-CoA is also a lipid precursor in cytosol and a substrate of protein acetylation in ER, both essential for myelin formation, I hypothesized that the transfer of citrate to the cytosol, via the transporter SLC25A1, and acetyl-CoA uptake to the ER, via the transporter SLC33A1, supports myelination. To evaluate this model, I further developed an inducible mouse model of overexpression of SLC25A1 or SLC33A1 in newly formed OL, using a tetracycline inducible system. When over-expression in mice is activated during the second postnatal week, in mice over-expressing SLC25A1 I detect a reduction of myelin protein levels suggesting altered late stages of OL differentiation and myelination. Conversely, in mice over-expressing SLC33A1 I detected higher myelin protein levels in the brain, suggestive of enhanced myelin formation. Together, these results highlight a significant role for acetyl-CoA metabolism and intracellular transport for myelin formation and provide insight to OPCs as sensors of specific metabolite abundance at subcellular resolution.

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