Redox Regulation, Protein S-nitrosylation, and Synapse Loss in Alzheimer's and Related Dementias

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2024 Nov 8

PMID 39515322

Authors

Chang-Ki Oh

Tomohiro Nakamura

Xu Zhang

Stuart A Lipton

Affiliations

Soon will be listed here.

Abstract

Redox-mediated posttranslational modification, as exemplified by protein S-nitrosylation, modulates protein activity and function in both health and disease. Here, we review recent findings that show how normal aging, infection/inflammation, trauma, environmental toxins, and diseases associated with protein aggregation can each trigger excessive nitrosative stress, resulting in aberrant protein S-nitrosylation and hence dysfunctional protein networks. These redox reactions contribute to the etiology of multiple neurodegenerative disorders as well as systemic diseases. In the CNS, aberrant S-nitrosylation reactions of single proteins or, in many cases, interconnected networks of proteins lead to dysfunctional pathways affecting endoplasmic reticulum (ER) stress, inflammatory signaling, autophagy/mitophagy, the ubiquitin-proteasome system, transcriptional and enzymatic machinery, and mitochondrial metabolism. Aberrant protein S-nitrosylation and transnitrosylation (transfer of nitric oxide [NO]-related species from one protein to another) trigger protein aggregation, neuronal bioenergetic compromise, and microglial phagocytosis, all of which contribute to the synapse loss that underlies cognitive decline in Alzheimer's disease and related dementias.

References

Ramirez-Mendoza A, Mendoza-Magana M, Ramirez-Herrera M, Hernandez-Nazara Z, Dominguez-Rosales J . Nitrooxidative Stress and Neuroinflammation Caused by Air Pollutants Are Associated with the Biological Markers of Neurodegenerative Diseases. Antioxidants (Basel). 2024; 13(3). PMC: 10968023. DOI: 10.3390/antiox13030326. View

Lui H, Zhang J, Makinson S, Cahill M, Kelley K, Huang H . Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell. 2016; 165(4):921-35. PMC: 4860138. DOI: 10.1016/j.cell.2016.04.001. View

Gentile J, Carrizales M, Koleske A . Control of Synapse Structure and Function by Actin and Its Regulators. Cells. 2022; 11(4). PMC: 8869895. DOI: 10.3390/cells11040603. View

Stamler J, Simon D, Osborne J, Mullins M, Jaraki O, Michel T . S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc Natl Acad Sci U S A. 1992; 89(1):444-8. PMC: 48254. DOI: 10.1073/pnas.89.1.444. View

Qu Z, Meng F, Bomgarden R, Viner R, Li J, Rogers J . Proteomic quantification and site-mapping of S-nitrosylated proteins using isobaric iodoTMT reagents. J Proteome Res. 2014; 13(7):3200-11. PMC: 4084841. DOI: 10.1021/pr401179v. View

Vargas J, Grudina C, Zurzolo C . The prion-like spreading of α-synuclein: From in vitro to in vivo models of Parkinson's disease. Ageing Res Rev. 2019; 50:89-101. DOI: 10.1016/j.arr.2019.01.012. View

Terry R, Masliah E, Salmon D, Butters N, DeTeresa R, Hill R . Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991; 30(4):572-80. DOI: 10.1002/ana.410300410. View

Sen N, Snyder S . Neurotrophin-mediated degradation of histone methyltransferase by S-nitrosylation cascade regulates neuronal differentiation. Proc Natl Acad Sci U S A. 2011; 108(50):20178-83. PMC: 3250167. DOI: 10.1073/pnas.1117820108. View

Hamilton R . Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol. 2000; 10(3):378-84. PMC: 8098522. DOI: 10.1111/j.1750-3639.2000.tb00269.x. View

10.

Leyns C, Holtzman D . Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener. 2017; 12(1):50. PMC: 5492997. DOI: 10.1186/s13024-017-0192-x. View

11.

Haendeler J, Hoffmann J, Tischler V, Berk B, Zeiher A, Dimmeler S . Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69. Nat Cell Biol. 2002; 4(10):743-9. DOI: 10.1038/ncb851. View

12.

Boulanger L . Immune proteins in brain development and synaptic plasticity. Neuron. 2009; 64(1):93-109. DOI: 10.1016/j.neuron.2009.09.001. View

13.

Liu K, Liu Z, Liu Z, Ma Z, Deng Y, Liu W . Manganese induces S-nitrosylation of PINK1 leading to nerve cell damage by repressing PINK1/Parkin-mediated mitophagy. Sci Total Environ. 2022; 834:155358. DOI: 10.1016/j.scitotenv.2022.155358. View

14.

Tsang A, Lee Y, Ko H, Savitt J, Pletnikova O, Troncoso J . S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease. Proc Natl Acad Sci U S A. 2009; 106(12):4900-5. PMC: 2660786. DOI: 10.1073/pnas.0810595106. View

15.

DE Santis A, Loguercio C, Nardi G . The frog spinal cord: a model to study methanethiol-central nervous system interaction. Comp Biochem Physiol C Comp Pharmacol Toxicol. 1990; 96(1):115-8. DOI: 10.1016/0742-8413(90)90054-d. View

16.

Umanah G, Ghasemi M, Yin X, Chang M, Kim J, Zhang J . AMPA Receptor Surface Expression Is Regulated by S-Nitrosylation of Thorase and Transnitrosylation of NSF. Cell Rep. 2020; 33(5):108329. PMC: 7737632. DOI: 10.1016/j.celrep.2020.108329. View

17.

Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar M, Okamoto S . Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A. 2013; 110(27):E2518-27. PMC: 3704025. DOI: 10.1073/pnas.1306832110. View

18.

Ischiropoulos H, Beckman J . Oxidative stress and nitration in neurodegeneration: cause, effect, or association?. J Clin Invest. 2003; 111(2):163-9. PMC: 151889. DOI: 10.1172/JCI17638. View

19.

Trudler D, Nazor K, Eisele Y, Grabauskas T, Dolatabadi N, Parker J . Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proc Natl Acad Sci U S A. 2021; 118(15). PMC: 8054017. DOI: 10.1073/pnas.2025847118. View

20.

Foster M, Forrester M, Stamler J . A protein microarray-based analysis of S-nitrosylation. Proc Natl Acad Sci U S A. 2009; 106(45):18948-53. PMC: 2776442. DOI: 10.1073/pnas.0900729106. View