The McDonough lab is focused on identifying neuroprotective therapies for multiple sclerosis (MS). Ongoing projects in the lab include investigating the role of changes in methionine metabolism and histone methylation in MS pathology. We have found that decreased levels of methyl donors S-adenosylmethionine and betaine are linked to mitochondrial defects in MS.
We also have exciting new data demonstrating 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.
Singhal N K , Li S, Arning E, Alkhayer K, Clements R, Sarcyk Z, Dassanayake R S, Brasch N E, Freeman E J, Bottiglieri T, McDonough J. (2015) Changes in Methionine Metabolism and Histone H3 Trimethylation are Linked to Mitochondrial Defects in Multiple Sclerosis, J. Neurosci. 35, 15170 –15186.
Li S, Clements R, Sulak M, Gregory R, Freeman E, McDonough J. (2013) Decreased NAA in Gray Matter is Correlated with Decreased Availability of Acetate in White Matter in Postmortem Multiple Sclerosis Cortex. Neurochem. Res., 38, 2385-2396.
Broadwater, L., Pandit, A., Clements, R., Azzam, S., Vadnal, J., Sulak, M., Yong, V.W., Freeman, E., Gregory, R., McDonough, J. (2011) Analysis of the mitochondrial proteome in multiple sclerosis cortex. Biochim. Biophys. Acta, 1812, 630-641.