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1,485 results on '"Lipton, Stuart"'

110. Correction for Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Author

Talantova, Maria, Sanz-Blasco, Sara, Zhang, Xiaofei, Xia, Peng, Akhtar, Mohd Waseem, Okamoto, Shu-ichi, Dziewczapolski, Gustavo, Nakamura, Tomohiro, Cao, Gang, Pratt, Alexander E., Kang, Yeon-Joo, Tu, Shichun, Molokanova, Elena, McKercher, Scott R., Hires, Samuel Andrew, Sason, Hagit, Stouffer, David G., Buczynski, Matthew W., Solomon, James P., Michael, Sarah, Powers, Evan T., Kelly, Jeffery W., Roberts, Amanda, Tong, Gary, Fang-Newmeyer, Traci, Parker, James, Holland, Emily A., Zhang, Dongxian, Nakanishi, Nobuki, Chen, H.-S. Vincent, Wolosker, Herman, Wang, Yuqiang, Parsons, Loren H., Ambasudhan, Rajesh, Masliah, Eliezer, Heinemann, Stephen F., Piña-Crespo, Juan C., and Lipton, Stuart A.

Published
2013

111. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Author

Talantova, Maria, Sanz-Blasco, Sara, Zhang, Xiaofei, Xia, Peng, Akhtar, Mohd Waseem, Okamoto, Shu-ichi, Dziewczapolski, Gustavo, Nakamura, Tomohiro, Cao, Gang, Pratt, Alexander E., Kang, Yeon-Joo, Tu, Shichun, Molokanova, Elena, McKercher, Scott R., Hires, Samuel Andrew, Sason, Hagit, Stouffer, David G., Buczynski, Matthew W., Solomon, James P., Michael, Sarah, Powers, Evan T., Kelly, Jeffery W., Roberts, Amanda, Tong, Gary, Fang-Newmeyer, Traci, Parker, James, Holland, Emily A., Zhang, Dongxian, Nakanishi, Nobuki, Chen, H.-S. Vincent, Wolosker, Herman, Wang, Yuqiang, Parsons, Loren H., Ambasudhan, Rajesh, Masliah, Eliezer, Heinemann, Stephen F., Piña-Crespo, Juan C., and Lipton, Stuart A.

Published
2013

114. Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Author

Cabral-Miranda, Felipe, Cabral-Miranda, Felipe, Tamburini, Giovanni, Martinez, Gabriela, Ardiles, Alvaro, Medinas, Danilo, Gerakis, Yannis, Hung, Mei-Li, Vidal, René, Fuentealba, Matias, Miedema, Tim, Duran-Aniotz, Claudia, Diaz, Javier, Ibaceta-Gonzalez, Cristobal, Sabusap, Carleen, Bermedo-Garcia, Francisca, Mujica, Paula, Adamson, Stuart, Vitangcol, Kaitlyn, Huerta, Hernan, Zhang, Xu, Nakamura, Tomohiro, Sardi, Sergio, Kennedy, Brian, Henriquez, Juan, Cárdenas, J, Plate, Lars, Palacios, Adrian, Hetz, Claudio, Lipton, Stuart, Cabral-Miranda, Felipe, Cabral-Miranda, Felipe, Tamburini, Giovanni, Martinez, Gabriela, Ardiles, Alvaro, Medinas, Danilo, Gerakis, Yannis, Hung, Mei-Li, Vidal, René, Fuentealba, Matias, Miedema, Tim, Duran-Aniotz, Claudia, Diaz, Javier, Ibaceta-Gonzalez, Cristobal, Sabusap, Carleen, Bermedo-Garcia, Francisca, Mujica, Paula, Adamson, Stuart, Vitangcol, Kaitlyn, Huerta, Hernan, Zhang, Xu, Nakamura, Tomohiro, Sardi, Sergio, Kennedy, Brian, Henriquez, Juan, Cárdenas, J, Plate, Lars, Palacios, Adrian, Hetz, Claudio, and Lipton, Stuart

Abstract

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Published
2022

119. Targeted protein S-nitrosylation of ACE2 as potential treatment to prevent spread of SARS-CoV-2 infection

Author

Oh, Chang-ki, primary, Nakamura, Tomohiro, additional, Beutler, Nathan, additional, Zhang, Xu, additional, Piña-Crespo, Juan, additional, Talantova, Maria, additional, Ghatak, Swagata, additional, Trudler, Dorit, additional, Carnevale, Lauren N., additional, McKercher, Scott R., additional, Bakowski, Malina A., additional, Diedrich, Jolene K., additional, Roberts, Amanda J., additional, Woods, Ashley K., additional, Chi, Victor, additional, Gupta, Anil K., additional, Rosenfeld, Mia A., additional, Kearns, Fiona L., additional, Casalino, Lorenzo, additional, Shaabani, Namir, additional, Liu, Hejun, additional, Wilson, Ian A., additional, Amaro, Rommie E., additional, Burton, Dennis R., additional, Yates, John R., additional, Becker, Cyrus, additional, Rogers, Thomas F., additional, Chatterjee, Arnab K., additional, and Lipton, Stuart A., additional

Published
2022
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126. Autistic Phenotype from MEF2C Knockout Cells

Author

Lipton, Stuart A., Li, Hao, Zaremba, Jeffrey D., McKercher, Scott R., Cui, Jiankun, Kang, Yeon-Joo, Nie, Zhiguo, Soussou, Walid, Talantova, Maria, Okamoto, Shu-Ichi, and Nakanishi, Nobuki

Published
2009

130. Behavioral Improvement in a Primate Parkinson's Model Is Associated with Multiple Homeostatic Effects of Human Neural Stem Cells

Author

Redmond,, D. Eugene, Bjugstad, Kimberly B., Teng, Yang D., Ourednik, Vaclav, Ourednik, Jitka, Wakeman, Dustin R., Parsons, Xuejun H., Gonzalez, Rodolfo, Blanchard, Barbara C., Kim, Seung U., Gu, Zezong, Lipton, Stuart A., Markakis, Eleni A., Roth, Robert H., Elsworth, John D., Sladek,, John R., Sidman, Richard L., and Snyder, Evan Y.

Published
2007
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145. Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models

Author

Marco, Sonia, Giralt, Albert, Petrovic, Milos M., Pouladi, Mahmoud A., Martinez-Turrillas, Rebeca, Martinez-Hernandez, Jose, Kaltenbach, Linda S., Torres-Peraza, Jesus, Graham, Rona K., Watanabe, Masahiko, Lujan, Rafael, Nakanishi, Nobuki, Lipton, Stuart A., Lo, Donald C., Hayden, Michael R., Alberch, Jordi, Wesseling, John F., and Perez-Otano, Isabel

Subjects
Gene expression -- Physiological aspects -- Research, Glutamate -- Models -- Physiological aspects -- Genetic aspects -- Research, Huntington's chorea -- Development and progression -- Genetic aspects -- Research, Biological sciences, Health
Abstract

Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully [...]

Published
2013
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146. Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome

Author

Wang, Xin, Zhao, Yingjun, Zhang, Xiaofei, Badie, Hedieh, Zhou, Ying, Mu, Yangling, Loo, Li Shen, Cai, Lei, Thompson, Robert C., Yang, Bo, Chen, Yaomin, Johnson, Peter F., Wu, Chengbiao, Bu, Guojun, Mobley, William C., Zhang, Dongxian, Gage, Fred H., Ranscht, Barbara, Zhang, Yun-wu, Lipton, Stuart A., Hong, Wanjin, and Xu, Huaxi

Subjects
Gene expression -- Research -- Analysis, Down syndrome -- Research -- Genetic aspects, Synapses -- Research -- Analysis, Biological sciences, Health
Abstract

Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that [Snx27.sup.-/-] mice have severe neuronal deficits in the hippocampus and cortex. Although [Snx27.sup.+/-] mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein β (C/EBPβ) in Down's syndrome brains and identify C/EBPβ as a transcription factor for SNX27. Down's syndrome causes overexpression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Down's syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome pathogenesis., SNX proteins comprise a large group of proteins that contain a conserved PX (or phagocyte oxidase homology) domain targeting SNX proteins to endosomes (1). SNX27 was originally identified in rats [...]

Published
2013
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148. Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease

Author

Nakamura, Tomohiro, Oh, Chang-Ki, Liao, Lujian, Zhang, Xu, Lopez, Kevin M, Gibbs, Daniel, Deal, Amanda K, Scott, Henry R, Spencer, Brian, Masliah, Eliezer, Rissman, Robert A, Yates, John R, and Lipton, Stuart A

Subjects
Dynamins, Aging, General Science & Technology, 1.1 Normal biological development and functioning, Neurodegenerative, Nitric Oxide, Alzheimer's Disease, Nitroarginine, Transgenic, Mice, Alzheimer Disease, Underpinning research, Acquired Cognitive Impairment, Animals, Humans, Cysteine, Protein Processing, Amyloid beta-Peptides, Animal, Post-Translational, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Cyclin-Dependent Kinase 5, Brain Disorders, HEK293 Cells, Synapses, Disease Models, Mutation, Neurological, Dementia, Nitric Oxide Synthase, Ubiquitin Thiolesterase, Oxidation-Reduction
Abstract

Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer's disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.

Published
2021

149. NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models.

Author

Ghatak, Swagata, Ghatak, Swagata, Dolatabadi, Nima, Gao, Richard, Wu, Yin, Scott, Henry, Trudler, Dorit, Sultan, Abdullah, Ambasudhan, Rajesh, Nakamura, Tomohiro, Masliah, Eliezer, Talantova, Maria, Voytek, Bradley, Lipton, Stuart A, Ghatak, Swagata, Ghatak, Swagata, Dolatabadi, Nima, Gao, Richard, Wu, Yin, Scott, Henry, Trudler, Dorit, Sultan, Abdullah, Ambasudhan, Rajesh, Nakamura, Tomohiro, Masliah, Eliezer, Talantova, Maria, Voytek, Bradley, and Lipton, Stuart A

Abstract

Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.

Published
2021

150. TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use.

Author

Doulias, Paschalis-Thomas, Doulias, Paschalis-Thomas, Nakamura, Tomohiro, Scott, Henry, McKercher, Scott R, Sultan, Abdullah, Deal, Amanda, Albertolle, Matthew, Ischiropoulos, Harry, Lipton, Stuart A, Doulias, Paschalis-Thomas, Doulias, Paschalis-Thomas, Nakamura, Tomohiro, Scott, Henry, McKercher, Scott R, Sultan, Abdullah, Deal, Amanda, Albertolle, Matthew, Ischiropoulos, Harry, and Lipton, Stuart A

Abstract

In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the pathogenesis of HIV-associated neurocognitive disorder (HAND) and further worsening cognitive activity in the setting of drug abuse. One consequence of such redox stress is aberrant protein S-nitrosylation, derived from nitric oxide, which may disrupt normal protein activity. Here, we report an improved, mass spectrometry-based technique to assess S-nitrosylated protein in human postmortem brains using selective enrichment of S-nitrosocysteine residues with an organomercury resin. The data show increasing S-nitrosylation of tricarboxylic acid (TCA) enzymes in the setting of HAND and HAND/meth use compared with HIV+ control brains without CNS pathology. The consequence is systematic inhibition of multiple TCA cycle enzymes, resulting in energy collapse that can contribute to the neuronal and synaptic damage observed in HAND and meth use.

Published
2021

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