Lee J. Martin, Ph.D.
Primary Appointment in Pathology; Secondary Appointment in Neuroscience
Member, Graduate Program in Neuroscience; Member, Graduate Program in Pathobiology
Mechanisms of Neuronal Death in Adult and Developing Central Nervous System. In the human central nervous system (CNS), neurons degenerate after acute neurological insults resulting from stroke and cardiac arrest and during the progression of adult-onset neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. Only certain groups of neurons degenerate in each of these neurological disorders, and this phenomenon is called selective vulnerability. In order to therapeutically manage and prevent this neurodegeneration, it is important to identify the cellular and molecular mechanisms of selective neuronal vulnerability and death. In my laboratory, we are testing the hypothesis that selective vulnerability is dictated by brain regional connectivity, mitochondrial function, and oxidative stress and is mediated by excitotoxic cell death resulting from abnormalities in excitatory, glutamatergic signal transduction pathways, including glutamate transporters and glutamate receptors as well as their downstream intracellular signaling molecules. We are also investigating the contribution of neuronal/glial apoptosis and necrosis as cell death pathways in animal (including transgenic mice) models of acute and progressive neurodegeneration. We use a variety of anatomical and molecular neurobiological approaches, including neuronal tract-tracing techniques, immunocytochemistry, immunoblotting, antipeptide antibody production, transmission electron microscopy, and DNA analysis to determine the precise regional and cellular vulnerabilities and the synaptic and molecular mechanisms that result in selective neuronal degeneration.
Martin LJ and Wong M. Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: A new target of disease mechanisms. Neurotherapeutics 10: 722-733, 2013.
Wong M, Gertz B, Chestnut BA and Martin LJ. Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Front. Cell. Neurosci. Dec 25;7:279. doi: 10.3389/fncel.2013.00279, 2013.
Martin LJ, Semenkow S, Hanaford A and Wong M. The mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice. Neurobiol. Aging 35:1132-1152, 2014.
Fayzullina A and Martin LJ. Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA). PLoS One. Mar 25;9(3):e93329. doi: 10.1371/journal.pone.0093329, 2014.
Martin LJ, Fancelli D, Wong M, Niedzwiecki M, Ballarini M, Plyte S and Chang Q. GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis. Front. Cell. Neurosci 8:433.doi: 10.3389/fncel.2014.00433, 2014.