Lipton Lab

Principal Investigator: Stuart Lipton, MD PhD  

email: slipton at scintillon dot org

Research Focus: Neurodegenerative and Neuromuscular Diseases, Alzheimer's Disease, Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease), HIV-Associated Dementia, Huntington's Disease, Parkinson's Disease, Stroke, Traumatic Injury, Spinal Cord Injury, Brain Injury

The Lipton laboratory studies molecular mechanisms of neurodegenerative diseases and stroke, including the role of excessive stimulation of ion channels and intracellular signaling pathways in nerve cells. Among the laboratory's accomplishments and ongoing activities are (i) the development of the first glutamate receptor/channel antagonist drug (Memantine), representing the most recent therapeutic to be clinically approved for the treatment of Alzheimer's disease by the European Union and the FDA, (ii) discovery with colleagues of the posttranslational protein modification termed S-nitrosylation (reaction of NO with a critical thiol group to control protein function), (iii) characterization of signaling events leading to neuronal injury and apoptosis in AIDS, and (iv) discovery and cloning of the transcription factor MEF2C that programs Embryonic Stem Cells to become nerve cells in the brain and whose knock down in the brain of rodents and humans causes Autism Spectrum Disorders (ASD). These studies have led to the development of the first neuroprotective drugs to be administered successfully to humans to combat various neurodegenerative and vascular diseases of the brain.


Stuart Lipton's Research Report

Developing Therapies to Prevent Neuronal Apoptosis

Our laboratory uses basic molecular signaling pathways to prevent neuronal apoptosis and to promote neuronal survival and outgrowth during normal aging and various neurodegenerative diseases, including cerebrovascular disease (stroke) and AIDS dementia. Neuronal damage is curtailed by preventing excessive activity of the NMDA subtype of glutamate receptor and its downstream effectors (see figure). Cultures of cerebrocortical neurons as well as transgenic and knock-out animal models are used to show the involvement of calcium, free radicals, caspases, and transcription factors in NMDA receptor-mediated neuronal apoptosis. Two NMDA antagonists that we have developed are clinically tolerated because they have been designed using biophysical principles to decrease only excessive NMDA receptor activity while leaving physiological levels of activity relatively spared - these drugs are now in clinical trials. Techniques used in the laboratory include patch-clamp recording, site-directed mutagenesis of recombinant NMDA receptor subunits and GABAC subunits, multi-photon confocal imaging of mitochondrial activities, deconvolution microscopy, gene reporter assays, and various fluorogenic methods for apoptosis assessment. 

Additionally, during the past few years we cloned and are currently characterizing two novel NMDA receptor subunits (one was recently published in Nature), and cloned a transcription factor, MEF2C, that controls the expression of NMDA receptor subunit genes and determines whether neurons undergo apoptosis after glutamate-related insults (recently published in PNAS and JBC). MEF2C is activated by the p38 stress kinase pathway, an active area of research in the laboratory that mediates both neuronal cell apoptosis and ischemic tolerance in the brain. 

Recently, we also discovered a new action of nitric oxide-related species on cysteine residues of the NMDA receptor. This reaction, termed S-nitrosylation (transfer of the NO group to critical cysteine sulfhydryls), down-regulates NMDA receptor activity as well as caspase activity and may be useful clinically. Several other protein targets of nitrosylation are being examined in the laboratory (recently published by us in Neuron and in Nature). 

We have also found a possible cause of neuronal apoptosis in AIDS brains (about one-third of AIDS patients eventually develop dementia). We discovered that the coat protein gp120 of HIV-1 produces a dramatic rise in neuronal calcium. This destructive process is primarily mediated by stimulation/activation of macrophage chemokine receptors by gp120 to release toxins that in turn trigger NMDA receptor-mediated neuronal destruction. Therefore, in some ways, this pathway resembles neuronal damage observed after stroke and other neurodegenerative diseases. (recently published in Nature, and Neuron, and JAMA). The involvement of apoptotic pathways in this type of cell death, involving reactive oxygen species, nitric oxide, mitochondrial toxins and caspases, is currently being explored. 

Complete List of Published Work:
http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/44150831/?sort=date&direction=as

research illustration

Schematic illustration of the signaling pathways discovered or characterized in the Neurodegenerative Disease Program that can be targeted to prevent neuronal apoptosis and thus treat various neurologic diseases. Drug or molecular therapies are being developed to (1) antagonize NMDA receptors (NMDA-Rc), (2) modulate activation of the p38 mitogen activated kinase (MAPK) - MEF2C (transcription factor) pathway, (3) prevent toxic reactions of free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), and (4) inhibit apoptosis-inducing enzymes including caspases


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Free radical attack on proteins can cause brain stress and loss of nerve cells in dementia

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