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4,207 results on '"Oh, Chang"'

21. Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection

Author

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

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Prevention, Coronaviruses Therapeutics and Interventions, Infectious Diseases, Lung, Coronaviruses, Emerging Infectious Diseases, 5.1 Pharmaceuticals, 2.2 Factors relating to the physical environment, Infection, Good Health and Well Being, Humans, COVID-19, SARS-CoV-2, Angiotensin-Converting Enzyme 2, Protein Binding, Peptidyl-Dipeptidase A, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy.

Published
2023

29. Inhibition of autophagic flux by S-nitrosylation of SQSTM1/p62 promotes neuronal secretion and cell-to-cell transmission of SNCA/α-synuclein in Parkinson disease and Lewy body dementia

Author

Oh, Chang-ki, Nakamura, Tomohiro, and Lipton, Stuart A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Dementia, Neurodegenerative, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Lewy Body Dementia, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Alzheimer's Disease Related Dementias (ADRD), Parkinson's Disease, Biotechnology, Brain Disorders, Stem Cell Research, Aging, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Neurological, Lewy body dementia, Parkinson’s disease, S-nitrosylation, autophagy, p62, α-synuclein
Abstract

Autophagy (in the form of macroautophagy) is the major intracellular protein quality control system for removal of damaged organelles and abnormally aggregated proteins. We and others have shown that dysregulated autophagic pathways contribute to accumulation and spread of misfolded proteins in many neurodegenerative disorders, including Parkinson disease (PD) and Lewy body dementia (LBD). Additionally, generation of excessive reactive oxygen and nitrogen species, such as nitric oxide (NO), accelerates neuronal and synaptic damage mediated, at least in part, via aberrant protein S-nitrosylation. Using cell-based models, including human induced pluripotent stem cell (hiPSC)-derived neurons, CRISPR-Cas9 technology, and transgenic PD/LBD mice, plus vetting in human postmortem brains, we found that S-nitrosylation of the autophagic receptor protein SQSTM1/p62 (forming SNO-SQSTM1/p62) inhibits autophagic flux, thus contributing to accumulation of misfolded SNCA/α-synuclein. Consequently, this impairment in autophagy increases extracellular vesicle-dependent secretion and spread of aggregated SNCA. Taken together, our evidence suggests that aberrant formation of SNO-SQSTM1/p62 represents a pathogenic event contributing not only to inhibition of autophagic flux and potentiation of neuronal damage, but also to propagation of α-synucleinopathy between cells in the diseased brain.

Published
2022

30. Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3

Author

Yang, Hongmei, Oh, Chang-Ki, Amal, Haitham, Wishnok, John S, Lewis, Sarah, Schahrer, Emily, Trudler, Dorit, Nakamura, Tomohiro, Tannenbaum, Steven R, and Lipton, Stuart A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, Alzheimer's Disease, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Aging, 2.1 Biological and endogenous factors, Neurological, Humans, Male, Female, Alzheimer Disease, Proteins, Brain, Protein Processing, Post-Translational, Synapses
Abstract

Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer's disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine (SNOTRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.

Published
2022

40. S-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders

Author

Kim, Ki-Ryeong, Cho, Eun-Jung, Eom, Jae-Won, Oh, Sang-Seok, Nakamura, Tomohiro, Oh, Chang-ki, Lipton, Stuart A, and Kim, Yang-Hee

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurodegenerative, Neurosciences, Dementia, Aging, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Neurological, Animals, Humans, Mice, Cathepsin B, Protein Aggregates, Neurodegenerative Diseases, Proteins, Alzheimer Disease, Cysteine, Nitric Oxide, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Protein S-nitrosylation is known to regulate enzymatic function. Here, we report that nitric oxide (NO)-related species can contribute to Alzheimer's disease (AD) by S-nitrosylating the lysosomal protease cathepsin B (forming SNO-CTSB), thereby inhibiting CTSB activity. This posttranslational modification inhibited autophagic flux, increased autolysosomal vesicles, and led to accumulation of protein aggregates. CA-074Me, a CTSB chemical inhibitor, also inhibited autophagic flux and resulted in accumulation of protein aggregates similar to the effect of SNO-CTSB. Inhibition of CTSB activity also induced caspase-dependent neuronal apoptosis in mouse cerebrocortical cultures. To examine which cysteine residue(s) in CTSB are S-nitrosylated, we mutated candidate cysteines and found that three cysteines were susceptible to S-nitrosylation. Finally, we observed an increase in SNO-CTSB in both 5XFAD transgenic mouse and flash-frozen postmortem human AD brains. These results suggest that S-nitrosylation of CTSB inhibits enzymatic activity, blocks autophagic flux, and thus contributes to AD pathogenesis.

Published
2022

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