Abnormal excitability contributes to neurologic disease pathogenesis either by impairing cell function or by increasing cellular susceptibility to injury. In most neurologic diseases, the pathologic process does not involve the entire neuromuscular unit. Instead, only specific subsets of neurons, glial cells, or muscle fibers are injured or die, and the nature of this selective injury determines the symptoms and clinical course of each disease. The long-term goal of our laboratory is to elucidate how ion channel signaling and synaptic plasticity contribute to the selective vulnerability of different cell populations and thus influence onset and/or progression of different neurologic disorders. To accomplish this goal, we use cell culture and mouse models and a combination of different approaches (molecular and cell biology, immunohistochemistry, in situ hybridization, imaging, biochemistry, and electrophysiology) to investigate two distinct but related areas:
(1) The function of intrinsic antioxidant signaling in the brain and skeletal muscle. Our aim is to define the role of endogenous antioxidant pathways in neuronal susceptibility to cell death, to elucidate how these pathways are regulated by neuronal activity, and to determine how these pathways modulate ion channel signaling in neurons, glia, and skeletal muscle fibers. Our current focus is on the Keap1/Nrf2/ARE pathway, which regulates the coordinated expression of a battery of antioxidant and phase II detoxification enzymes in response to a mild oxidative or ER stress in many different tissues, including the brain and skeletal muscle.
(2) Autophagy impairment and neurologic disease. In animal models, autophagy deficiency results in neurodegeneration and skeletal muscle atrophy; little, however, is known about the role of autophagy in normal neurologic function. We seek to elucidate why the consequences of autophagy deficiency (failure of autophagy initiation) and autophagy impairment (block of autophagy completion) differ in the skeletal muscle but are the same in the brain, to determine how autophagy regulates intrinsic antioxidant pathways and cellular excitability, and to establish how autophagy failure contributes to neuromuscular disease pathogenesis.
Our laboratory is also pursuing translational research with a goal to improve tissue-based diagnostics of neuromuscular diseases. To learn more about ongoing basic and translational research projects, please visit our lab Website.
1. Hahn J, Wang X and Margeta M. Glial regulation of neuronal NMDA receptor activity. In preparation for submission (2013).
2. Habas A, Wang X, Hahn J and Margeta M. Neuronal activity regulates astrocytic Nrf2 signaling. In revision for PNAS (2013).
3. Chandiramani N, Wang X, and Margeta M. Molecular basis for vulnerability to mitochondrial and oxidative stress in a neuroendocrine CRI-G1 cell line. PLoS One, 2011; 6:e14485.
4. Margeta-Mitrovic M, Jan YN and Jan LY. A trafficking checkpoint controls GABA(B) receptor heterodimerization. Neuron, 2000; 27:97-106.
1. Hiniker A, Daniels BH, Lee HS and Margeta M. Comparative utility of LC3, p62 and TDP-43 immunohistochemistry in differentiation of inclusion body myositis from polymyositis and related inflammatory myopathies. Acta Neuropathol Commun, 2013; 1:29.
2. Daniels BH, McComb RD, Mobley BC, Gultekin SH, Lee HS and Margeta M. LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar cardiomyopathy: A study of three cases. Am J Surg Pathol, 2013; 37:1014-21.
3. Lee HS, Daniels BH, Salas E, Bollen AW, Debnath J, and Margeta M. Clinical utility of LC3 and p62 immunohistochemistry in diagnosis of drug-induced autophagic vacuolar myopathies: A case-control study. PloS One, 2012; 7:e36221.
4. Layzer R, Lee H, Iverson D and Margeta M. Dermatomyositis with inclusion body myositis pathology. Muscle Nerve, 2009; 40:469-71.