Stuart Lipton, MD, PhD
Scripps Research Joint Appointments
Other Joint Appointments
Professor (adjunct), Department of Neurosciences, University of California, San Diego, School of MedicineProfessor (adjunct), Department of Neurology, Yale School of Medicine
Research Focus
Dr. Lipton is best known for first describing the mechanism of action and contributing to the clinical development of the FDA-approved Alzheimer’s drug, memantine (Namenda®, NamendaXR®, Namzaric®), and for discovering the posttranslational redox modification known as protein S-nitrosylation. Recently, Lipton and colleagues combined memantine with S-nitrosylation chemistry to produce a new drug called NitroSynapsin, which displays disease-modifying activity in animal models of Alzheimer’s disease, both protecting synapses and improving neurobehavioral deficits. Lipton’s group also characterized HIV-related pathways to neuronal damage, discovered the NR3 (now known at GluN3) family of modulatory NMDA-type glutamate receptor subunits in the brain, characterized the molecular pathways for protecting neurons with Erythropoietin, and discovered the transcription factor MEF2C. His group showed that MEF2C activity is regulated by S-nitrosylation and serves as a master switch for neurogenesis from human neural stem cells. Dysregulated MEF2C is involved in the pathogenesis of Parkinson’s disease, Alzheimer’s disease, Autism-Spectrum Disorder, and Vascular dementia.
Ongoing research in the lab is focused on 2D human induced pluripotent stem cell (hiPSC)-derived cultures and 3D cerebral organoid models of neurodegenerative and neurodevelopmental disease and aberrant redox/S-nitrosylation pathways leading to synaptic damage. Using these approaches, the Lipton group is developing novel drugs to combat Alzheimer’s disease (AD), Parkinson’s disease (PD), Vascular dementia (VaD), and other neurodegenerative disorders, as well as Autism-Spectrum Disorder (ASD) and Intellectual and Developmental Disabilities (IDD). Tissue culture models complement whole-animal approaches. A plethora of techniques is employed, including chemical biology, molecular biology, patch-clamp electrophysiology, calcium imaging, and neurobehavioral paradigms.
Education
B.A., Neurobiology and Immunology, Cornell UniversityM.D., Medicine, University of Pennsylvania
Ph.D., Biochemistry & Biophysics, University of Pennsylvania (thesis research at Harvard University)
Professional Experience
Neurologist/neuroscientist Stuart Lipton, MD, PhD is a renowned expert in dementia. He was trained at Cornell University, the University of Pennsylvania, and Harvard University. In addition to running a basic-science laboratory at The Scripps Research Institute, he has an active clinical neurology practice at UC San Diego focusing on dementia and general neurology. Lipton completed his PhD thesis research with John Dowling at Harvard, followed by clinical residency and a postdoctoral fellowship at Harvard with Torsten Wiesel during the time that Wiesel won the Nobel prize. He was then on the Harvard faculty for over 20 years before moving to La Jolla as founding director of a new neuroscience center in 2000.
Awards & Professional Activities
HONORS & RECOGNITION•NIH Director's Grant Award
National Institutes of Health/NIDA (2016)
•Elected Fellow, American Association for the Advancement of Science
Neuroscience section (2011)
•Ernst Jung Prize in Medicine (2004)
•Alpha Omega Alpha Medical Honor Society (1974)
•Phi Beta Kappa (1971)
PROFESSIONAL SERVICE
•Society for Neuroscience (2000 - 2008)
Chair of Education Committee and Neurobiology of Disease Workshops
•American Academy of Neurology (2000)
Fellow
•American Neurological Association (1987)
Elected Fellow
Selected References
Lipton SA, Choi Y-B. . . Chen H-SV, Sucher NJ, Singel DJ, Loscalzo J, Stamler JS. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993;364:626-632.
Leifer D, Krainc D, Yu Y-T, McDermott J, Breitbart RE, Heng J, Neve RL, Kosofsky B, Nadal-Ginard B, Lipton SA. MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex. Proc Natl Acad Sci USA 1993;90:1546-1550.
Das S, Sasaki YF. . . Chen H-SV, Lipton SA, Nakanishi N. Increased NMDA current and spine density in mice lacking the NMDAR subunit NR3A. Nature 1998;393:377-381.
Choi Y-B, Tenneti L, Le DA, Ortiz J, Bai G, Chen H-SV, Lipton SA. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nature Neurosci 2000;3:15-21.
Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV dementia. Nature 2001;410:988-94.
Digicaylioglu M, Lipton SA. Erythropoietin mediates neuroprotection via cross-talk between the Jak2 and NF-kB signalling cascades. Nature 2001;412:641-647.
Chatterton JE. . . Nakanishi N, Tong G, Lipton SA, Zhang D. Excitatory glycine receptor containing the NR3 family of NMDA receptor subunits. Nature 2002;415:793-798.
Gu Z, Kaul M. . . Strongin A, Smith JW, Liddington RC, Lipton SA. S-Nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 2002;297:1186-1190.
Lipton SA. Turning down but not off—paradigm shift in neuroprotective drug development. Nature 2004;428:473.
Yao D, Gu Z. . . Lipton SA. Nitrosative stress linked to sporadic Parkinson’s disease: S-Nitrosylation of parkin regulates it E3 ligase activity. Proc Natl Acad Sci USA 2004;101:10810-10814; Comment by Lipton SA et al., Science 2005;308:1870.
Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nature Rev Drug Disc 2006;5:160-170.
Uehara T. . . Gu Z, Masliah E, Nomura Y, Lipton SA. S-Nitrosylation of protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 2006;441:513-517.
Li H, Radford, JC, Ragusa MJ, Shea KL, McKercher SR, Zaremba J, Soussou W, Nie Z. . . Lipton SA. Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci USA 2008;1-5:9397-402.
Lipton SA, Li H, Zaremba JD, McKercher SR, Cui J. . . Soussou W, Talantova M, Okamoto S, Nakanishi N. Autistic phenotype from MEF2C knockout cells. Science 2009;323:208.
Cho D-H, Nakamura T. . . Godzik A, Gu Z, Lipton SA. S-Nitrosylation of Drp1 mediates β-amyloid-related mitochondrial fission and neuronal injury. Science 2009;324:102-105.
Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA*, Ding S*. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 2011;9:113-118 (*co-corresponding authors).
Ryan SD. . . Jaenisch R, Ambasudhan R, Lipton SA. Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 2013:155;1351–1364.
Sunico CR. . . Ambasudhan R, Nakanishi N, Lipton SA. Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons. Proc Natl Acad Sci USA 2016;113: E7564-E7571.
Akhtar MW. . . McKercher SR, Ambasudhan R, Nakamura T, Lipton SA. Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation. Nature Commun 2016;7:10242.
Nagar S, Noveral SM, Trudler D, Lopez K, McKercher SR. . . Lipton SA. MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress. Proc Natl Acad Sci USA 2017;114:E4048-E4056.
Tu S, Akhtar MW, Escorihuela RM, Amador-Arjona A, Swarp V, Parker J, Zaremba JD, Holland T, Bansal N, Holoham DR, Lopez K, Ryan SD, Chan SF, Yan L, Zhang X, Huang X, Sultan A, McKercher SR, Ambasudhan R, Xu H, Wang Y, Geschwind DH, Roberts AJ, Terskikh AV, Masliah E, Lipton SA, Nakanishi N. NitroSynapsin therapy for the mouse MEF2C haploinsufficiency model of human autism. Nature Commun 2017;8:1488.
Ryan T, Bamm VV, Stykel MG, Coackley CL, Humphries KM, Jamieson-Williams R, Ambasudhan R, Mosser DD, Lipton SA, Harauz G, Ryan SD. Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein proteostasis in hPSC-derived Parkinson’s disease neurons. Nature Commun 2018;9:817.
Ghatak S, Dolatabadi N, Trudler D, Zhang XT, Wu Y, Mohata M, Ambasudhan R, Talantova M, Lipton SA. Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls. eLIFE 2019 Nov 29;8. pii: e50333.
Ghatak S, Dolatabadi N, Gao R, Wu Y, Scott H, Trudler D, Sultan A, Ambasudhan R, Nakamura T, Masliah E, Talantova M, Voytek B, Lipton SA. NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models. Mol Psychiatry 2020;10.1038/s41380-020-0776-7.
Nakamura T, Oh CK, Liao L, Zhang X, Lopez KM, Gibbs D, Deal AK, Scott HR, Spencer B, Masliah E, Rissman RA, Yates JR 3rd, Lipton SA. Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease. Science 2021;371(6526);eaaw0843. doi: 10.1126/science.aaw0843.
Pirie E, Oh CK, Zhang X, Han X, Cieplak P, Scott HR, Deal AK, Ghatak S, Martinez FJ, Yeo GW, Yates JR 3rd, Nakamura T, Lipton SA. S-Nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD. Proc Natl Acad Sci USA 2021 Mar 16;118(11):e2021368118.
Trudler D, Nazor KL, Eisele YS, Grabauskas T, Dolatabadi N, Parker J, Sultan A, Zhong Z, Goodwin MS, Levites Y, Golde TE, Kelly JW, Sierks MR, Schork NJ, Karin M, Ambasudhan R, Lipton SA. Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proc Natl Acad Sci USA 2021 Apr 13;118(15):e2025847118.
Links
Link to all publications (h-index = 143)
UCSD Neurosciences Graduate School Program