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RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS
Open accessAbstract
Axonal pathology and necroptosis in ALS: Necroptosis, a non–caspase-dependent form of cell death, can be reduced in disease states by inhibiting a kinase called RIPK1. Until now, no human mutations have been linked to necroptosis. Ito et al. show that loss of optineurin, which is encoded by a gene that has been implicated in the human neurodegenerative disorder ALS (amyotrophic lateral sclerosis), results in sensitivity to necroptosis and axonal degeneration. When RIPK1-kinase dependent signaling is disrupted in mice that lack optineurin, necroptosis is inhibited and axonal pathology is reversed. Science , this issue p. 603
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“Moreover, it has recently been reported that the autophagic receptor optineurin (OPTN) [509] actively regulates the proteasomal turnover of RIPK1, as the loss of OPTN induces axonal degeneration via RIPK1-dependent necroptosis [510].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [510]
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RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation
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“Yet, this notion has also been challenged based on negative results and recently a form of programmed cell death termed “necroptosis” - programmed necrosis, was suggested to drive degeneration in ALS (He and Strong, 2000; Ito et al., 2016; Re et al., 2014; Yamazaki et al., 2005).”
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“To assess activation of necroptotic signaling, we assayed levels and phosphorylation of RIPK3 and MLKL, two essential proteins for necroptosis (Ofengeim et al., 2015; Caccamo et al., 2017; Ito et al., 2016; Vitner et al., 2014).”
BackgroundMethodRIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis
Zelic, M., Pontarelli, F., Woodworth, L. A., Zhu, C., Mahan, A. L., Ren, Y., LaMorte, M. J., Gruber, R. C., Keane, A. M., Loring, P., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109112 · Cited by 138
“, 2017), amyotrophic lateral sclerosis (ALS) (Ito et al., 2016; Xu et al., 2018), Niemann-Pick disease type C (Cougnoux et al.”
Self-citationCrashing the computer: apoptosis vs. necroptosis in neuroinflammation
Heckmann, B. L., Tummers, B., & Green, D. R. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0195-3 · Cited by 136
Park, J., Ha, H.-J., Chung, E. S., Baek, S. H., Cho, Y., Kim, H. K., Han, J., Sul, J. H., Lee, J., Kim, E., et al. (2021) · Science Advances · doi:10.1126/sciadv.abd3207 · Cited by 139
Necroptosis: A Novel Pathway in Neuroinflammation
Yu, Z., Jiang, N., Su, W., & Zhuo, Y. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.701564 · Cited by 134
“Necroptosis has been reported to play a crucial role in the pathogenesis of certain neuroinflammatory disorders (Ito et al., 2016; Chia et al., 2018; Zhang et al., 2019).”
BackgroundBehl, T., Makkar, R., Sehgal, A., Singh, S., Sharma, N., Zengin, G., BUNGAU, S. G., Andronie-Cioară, F. L., Munteanu, M. A., Brisc, M. C., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147432 · Cited by 134
The potential role of necroptosis in inflammaging and aging
Royce, G. H., Brown‐Borg, H. M., & Deepa, S. S. (2019) · GeroScience · doi:10.1007/s11357-019-00131-w · Cited by 137
“Using two mouse models of ALS [optineurin-deficient mice (Optn− /−) and SOD1G93A transgenic mice], Ito et al. (2016) showed that necroptosis was increased in oligodendrocytes in the ALS mice and that blocking necroptosis either genetically (Ripk3−/− and/or Ripk1D138N/D138N mice) or…”
BackgroundMethodInfluentialGenetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy
Suzuki, N., Nishiyama, A., Warita, H., & Aoki, M. (2022) · Journal of Human Genetics · doi:10.1038/s10038-022-01055-8 · Cited by 148
“Both alsin and optineurin are autophagy-related molecules, suggesting that disruption of the protein degradation machinery is involved in the pathogenesis of ALS [18, 19].”
BackgroundTAM Kinases Promote Necroptosis by Regulating Oligomerization of MLKL
Najafov, A., Mookhtiar, A. K., Luu, H. S., Ordureau, A., Pan, H., Amin, P. P., Li, Y., Lu, Q., & Yuan, J. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.05.022 · Cited by 134
Self-citationThe necroptosis machinery mediates axonal degeneration in a model of Parkinson disease
Oñate, M., Catenaccio, A., Salvadores, N., Saquel, C., Martinez, A. N., Moreno‐González, I., Gamez, N., Rudolffi-Soto, P., Soto, C. A., Hetz, C. A., et al. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0408-4 · Cited by 133
“Similarly, in a mouse model of ALS, oligodendrocytes showed greater sensitivity to TNFα-induced cell death, and microglia showed increased phosphorylation of RIPK1 and increased expression of a number of inflammatory genes (Ito et al., 2016).”
BackgroundInfluentialYoshikawa, M., Saitoh, M., Katoh, T., Seki, T., Bigi-Botterill, S. V., Shimizu, Y., Ishii, T., Okai, T., Kuno, M., Hattori, H., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01647 · Cited by 129
Béland, L.-C., Markovinovic, A., Jakovac, H., De Marchi, F., Bilic, E., Mazzini, L., Kriz, J., & Munitic, I. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa124 · Cited by 125
“mutations or haploinsufficiency of TANK-binding kinase 1 (TBK1) and optineurin (encoded by OPTN gene) lack overt microgliosis and astrocytosis (Ito et al., 2016; Gerbino et al., 2020).”
BackgroundGeneration of a Motor Nerve Organoid with Human Stem Cell-Derived Neurons
Kawada, J., Kaneda, S., Kirihara, T., Maroof, A. M., Levi, T., Eggan, K. C., Fujii, T., & Ikeuchi, Y. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.09.021 · Cited by 123
“Importantly, axon fascicles are often damaged by neurodegenerative diseases (Ito et al., 2016).”
BackgroundThe regulation of necroptosis by post-translational modifications
Meng, Y., Sandow, J. J., Czabotar, P. E., & Murphy, J. M. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-020-00722-7 · Cited by 130
Regulated cell death: discovery, features and implications for neurodegenerative diseases
Cui, J., Zhao, S., Li, Y., Zhang, D., Wang, B., Xie, J., & Wang, J. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00799-8 · Cited by 130
Self-citationRIPK 3 in cell death and inflammation: the good, the bad, and the ugly
Orozco, S. L., & Oberst, A. (2017) · Immunological Reviews · doi:10.1111/imr.12536 · Cited by 122
Autophagy regulates inflammatory programmed cell death via turnover of RHIM-domain proteins
Lim, J., Park, H., Heisler, J., Maculins, T., Roose‐Girma, M., Xu, M., McKenzie, B. S., Campagne, M. V. L., Newton, K., & Murthy, A. (2019) · eLife · doi:10.7554/elife.44452 · Cited by 121
“…protein inducing interferon b (TRIF) and innate sensor Z-DNA binding protein 1 (ZBP1) can directly interact with RIPK1 and/or RIPK3 via their RHIM domains, thereby stabilizing downstream signaling (He et al., 2011; Kaiser et al., 2013; Lin et al., 2016; Newton et al., 2016; Thapa et al., 2016).”
InfluentialIntersections between Regulated Cell Death and Autophagy
Napoletano, F., Baron, O., Vandenabeele, P., Mollereau, B., & Fanto, M. (2019) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.12.007 · Cited by 120
Dong, Y., Yu, H., Li, X., Bian, K., Zheng, Y., Dai, M., Feng, X., Sun, Y., He, Y. T., Yu, B., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02567-y · Cited by 127
Wang, H., Meng, H., Li, X., Zhu, K., Dong, K., Mookhtiar, A. K., Wei, H., Li, Y., Sun, S., & Yuan, J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1715742114 · Cited by 118
Self-citationmiR-425 deficiency promotes necroptosis and dopaminergic neurodegeneration in Parkinson’s disease
Hu, Y.-B., Zhang, Y., Wang, H., Ren, R., Cui, H., Huang, W., Cheng, Q., Chen, H., & Wang, G. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1809-5 · Cited by 120
Self-citationCell Death and NeurodegenerationPreprint
Andreone, B. J., Larhammar, M., & Lewcock, J. W. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a036434 · Cited by 124
“Several reports indicate that RIPK signaling contributes to neuronal loss in various in vivo mod- 2 Cite this article as Cold Spring Harb Perspect Biol 2020;12:a036434 els (Ito et al. 2016; Caccamo et al. 2017; Yang et al. 2017; Zhang et al. 2017; Iannielli et al. 2018).”
BackgroundDysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma
Toth, R. P., & Atkin, J. D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01017 · Cited by 114
“In addition, during the inflammatory response, optineurin interacts with interleukin-1 receptor-associated kinase-1 (IRAK1) (61), receptor-interacting protein kinase-1 (RIPK-1) (62), and ubiquitin carboxylterminal hydrolase (CYLD) (63).”
BackgroundInfluentialLi, F., Xu, D., Wang, Y., Zhou, Z., Liu, J., Hu, S., Gong, Y., Yuan, J., & Pan, L. (2018) · Autophagy · doi:10.1080/15548627.2017.1391970 · Cited by 120
Self-citationROS-Mediated Necroptosis Is Involved in Iron Overload-Induced Osteoblastic Cell Death
Tian, Q., Qin, B., Gu, Y., Zhou, L., Chen, S., Zhang, S., Zhang, S., Han, Q., Liu, Y., & Wu, X. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/1295382 · Cited by 116
“Eventually, the phosphorylated MLKL undergoes oligomerization and translocates to the plasma membrane to execute necroptotic cell death [18, 29].”
BackgroundSmall-Molecule Inhibitors of Necroptosis: Current Status and Perspectives
Zhuang, C., & Chen, F. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01317 · Cited by 116
Disease-modifying therapies in amyotrophic lateral sclerosis
Chiò, A., Mazzini, L., & Mora, G. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.107986 · Cited by 123
Vissers, M. F. J. M., Heuberger, J. A. A. C., Groeneveld, G. J., Nijhuis, J. O., Deyn, P. P. D., Hadi, S., Harris, J. M., Tsai, R. M., Cruz-Herranz, A., Huang, F., et al. (2022) · Clinical and Translational Science · doi:10.1111/cts.13317 · Cited by 116
Agujetas, V. R., Barbero‐Camps, E., de Dios, C., Podlesniy, P., Abadin, X., Morales, A., Marı́, M., Trullás, R., & Colell, A. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00435-6 · Cited by 113
The in vivo evidence for regulated necrosis
Tonnus, W., & Linkermann, A. (2017) · Immunological Reviews · doi:10.1111/imr.12551 · Cited by 114
miRNA-21 ablation protects against liver injury and necroptosis in cholestasis
Afonso, M. B., Rodrigues, P. M., Simão, A. L., Gaspar, M. M., Carvalho, T., Borralho, P., Bañales, J. M., Castro, R. E., & Rodrigues, C. M. P. (2017) · Cell Death and Differentiation · doi:10.1038/s41418-017-0019-x · Cited by 109
A decade of cell death studies: Breathing new life into necroptosis
Khan, I., Yousif, A., Chesnokov, M. S., Hong, L., & Chefetz, I. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107717 · Cited by 113
New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases
Scarian, E., Viola, C., Dragoni, F., Gerlando, R. D., Rizzo, B., Diamanti, L., Gagliardi, S., Bordoni, M., & Pansarasa, O. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052698 · Cited by 118
“As well as microglia, astrocytes exert toxic effects on MNs by secreting pro-inflammatory molecules, including NO, NOX2, prostaglandin E2, and leukotriene B4, or inducing necroptosis [188–191].”
BackgroundMultitasking Kinase RIPK1 Regulates Cell Death and InflammationPreprint
Newton, K. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a036368 · Cited by 107
“2016), amyotrophic lateral sclerosis (Ito et al. 2016), aortic aneurysm (Wang et al.”
Background
Metadata
- Authors
- Ito, Y., Ofengeim, D., Najafov, A., Das, S., Saberi, S., Li, Y., Hitomi, J., Zhu, H., Chen, H., Mayo, L., Geng, J., Amin, P., DeWitt, J. P., Mookhtiar, A. K., Florez, M., Ouchida, A. T., Fan, J.-B., Pasparakis, M., Kelliher, M. A., Ravits, J., & Yuan, J.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Brigham and Women's Hospital (US)
- Illumina (United States) (US)
- University of Cologne (DE)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Yuan, Junying
- ORCID
- Venue
- Science
- Published
- 2016-08-05
- Volume
- 353
- Issue
- 6299
- Pages
- 603-608
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5444917
- OpenAlex
- W2500850723
- Cited by
- 606
- References
- 40
- Citations by year
- 2026: 43 · 2025: 59 · 2024: 66 · 2023: 74 · 2022: 58 · 2021: 79 · 2020: 74 · 2019: 57 · 2018: 55 · 2017: 33 · 2016: 6
- FWCI
- 38.10
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (1R01NS082257)
- National Institute on Aging (1R01AG047231)
- NIH
- National Science and Technology Major Project of China (2014ZX09102001-002)
- State Key Program of National Natural Science of China (31530041)
- National Institute of Allergy and Infectious Diseases (2RO1AI075118)
- European Research Council (323040)
- Daiichi Sankyo Foundation of Life Science
- The Nakatomi Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Japan Society for the Promotion of Science
- National Multiple Sclerosis Society
- National Multiple Sclerosis Society Career Transition Award
- Huazhong University of Science and Technology
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- amyotrophic lateral sclerosis, optineurin, RIPK1, RIPK3, MLKL, necroptosis, axonal degeneration, neuroinflammation, dysmyelination, SOD1 G93A mice, axonal protection
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Axons, Humans, Inflammation, Mice, Transgenic, Necrosis, Nerve Degeneration, Spinal Cord, Superoxide Dismutase, Suppression, Genetic, Apoptosis, Cell Cycle Proteins, Membrane Transport Proteins, Transcription Factor TFIIIA, Mice, Receptor-Interacting Protein Serine-Threonine Kinases
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