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RESEARCH PROJECTS

We study methionine metabolism and epigenetic mechanisms involved in neurodegenerative disease.
We have identified changes in methionine metabolism and availability of methyl donors SAM and betaine that impact histone methylation in neurodegenerative diseases, such as MS and AD.

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BHMT-BETAINE METHYLATION PATHWAY

We have found that methionine metabolism is dysregulated in MS due to the decreased enzymatic activity of methionine synthase, the enzyme that catalyzes the conversion of homocysteine to methionine. We recently discovered that betaine supplementation restores levels of S-adenosylmethionine (SAM, the major methyl donor for cellular reactions), and restores methylation on H3K4. This is accomplished through activation of the betaine homocysteine methyltransferase (BHMT)-betaine pathway wherein the BHMT enzyme uses betaine as the methyl donor and remethylates homocysteine to methionine. We have found that through this pathway we have the ability to alter chromatin conformation and modulate gene expression, highlighting a novel therapeutic target.

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HEMOGLOBIN BETA AND MS

We have found evidence that hemoglobin is expressed in both the cytoplasm and in the nucleus of pyramidal neurons in the human cortex.  We have identified hemoglobin interacting proteins in neurons by mass spectrometry and found that it interacts with mitochondria and with nuclear proteins including histones and a histone demethylase.  Our data suggest that hemoglobin signals between mitochondria and the nucleus to regulate neuronal energetics.  We have found that the subcellular localization of hemoglobin is dysregulated in MS and may contribute to mitochondrial impairment in this disease, making it a potential therapeutic target.

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DECREASED NAA IN MS BRAIN

N-acetylaspartate (NAA) is made by mitochondria in neurons. We have found that dysfunctional mitochondria in MS lead to a decrease in NAA in the grey matter, causing a subsequent decrease in acetate levels, which is necessary for myelin formation. These data suggest a novel mechanism whereby mitochondrial dysfunction and reduced NAA levels in neurons may result in compromised myelination by oligodendrocytes due to decreased availability of acetate necessary for the synthesis of myelin lipids.

Research: Research
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