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S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death.
Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, Smith JW, Liddington RC, Lipton SA
Science. 2002 Aug 16;297(5584):1186-90
Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.
Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D
Nature. 2002 Feb 14;415(6873):793-8
Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades.
Digicaylioglu M, Lipton SA
Nature. 2001 Aug 9;412(6847):641-7
Pathways to neuronal injury and apoptosis in HIV-associated dementia.
Kaul M, Garden GA, Lipton SA
Nature. 2001 Apr 19;410(6831):988-94
Stuart Lipton's 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
Watch Dr. Lipton describe his research
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.
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.
About Stuart Lipton
Stuart Lipton went to Cornell University, entered an M.D./Ph.D. Program at the University of Pennsylvania (UPENN), and completed his M.D. at UPENN and his Ph.D. with John Dowling at Harvard in 1977. He was then a medical intern and neurology resident at Harvard and a postdoctoral fellow of Torsten Wiesel when Wiesel won the Nobel prize in 1981. In 1997, after spending 15 years on the staff of Children's Hospital in Boston, Dr. Lipton moved to Brigham and Women's Hospital to become Chief of the CNS Research Institute at Harvard Medical School. Dr. Lipton was recruited to Sanford-Burnham Medical Research Institute in September 1999 as Professor and Director of the Del E.Webb Center for Neuroscience and Aging Research. At that time he initiated the Center's program on Neurodegenerative Disease Research.
Dr. Lipton has been interested in the role of ion channels in neuronal outgrowth, plasticity and survival. His group has developed several clinically-tolerated drugs to prevent neuronal damage and apoptosis due to excessive stimulation of ion channels by excitatory neurotransmitters acting at the NMDA subtype of glutamate receptor in the brain. These drugs may be useful for several neurological disorders, including stroke, spinal cord and head injury, glaucoma , Huntington's disease , and AIDS dementia. Drugs developed in his laboratory are currently in advanced clinical trials. Recently, Dr. Lipton was asked to deliver a Nobel Foundation Lecture at the Karolinska Institute and a plenary lecture at the National Academy of Sciences on the topic of NMDA open-channel blockers and nitric oxide-related drugs for the treatment of AIDS dementia, a field in which he continues to be among the leaders.