Stuart A. Lipton, MD, PhD
Professor
Department of Molecular and Cellular Biology
Step Family Foundation Endowed Chair; Founding Co-director, Neurodegeneration New Medicines Center
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.
Select Publications
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Lipton, Stuart A. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nature Reviews Drug Discovery 2006, 5, 160-170.
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Uehara, Takashi; Nakamura, Tomohiro; Yao, Dongdong; Shi, Zhong- Q.; Gu, Zezong; Ma, Yuliang; Masliah, Eliezer; Nomura, Yasuyuki; Lipton, Stuart A. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 2006, 441, 513-7.
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Cho, D. H.; Nakamura, T.; Fang, J. G.; Cieplak, P.; Godzik, A.; Gu, Z.; Lipton, Stuart A. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 2009, 324, 102-105.
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Ryan, S. D.; Dolatabadi, N.; Chan, S. F.; Zhang, X.; Akhtar, M. W.; Parker, J.; Soldner, F.; Sunico, C. R.; Nagar, S.; Talantova, M.; Lee, B.; Lopez, K.; Nutter, A.; Shan, B.; Molokanova, E.; Zhang, Y.; Han, X.; Nakamura, T.; Masliah, E.; Yates, John R.; Nakanishi, N.; Andreyev, A. Y.; Okamoto, S.; Jaenisch, R.; Ambasudhan, Rajesh; Lipton, Stuart A. Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1 alpha transcription. Cell 2013, 155, 1351-1364.
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Nakamura, T; Oh, C- K.; Liao, L; Zhang, X; Lopez, K M.; Gibbs, D; Deal, A K.; Scott, H R.; Spencer, B; Masliah, E; Rissman, R A.; Yates, J R.; Lipton, S A. Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease. Science 2021, 371.
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Yang, Hongmei; Amal, Haitham; Tannenbaum, Steven R.; Lipton, Stuart A. Proteome-wide profiling of S-nitrosylated proteins using the SNOTRAP probe and mass spectrometry-based detection. 2025.
