Cited by 611Amyotrophic Lateral Sclerosis ResearchCell death mechanisms and regulationHereditary Neurological Disorders

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RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

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Ito, Yasushi, Ofengeim, Dimitry, Najafov, Ayaz, Das, Sudeshna, Saberi, Shahram, Li, Ying, Hitomi, Junichi, Zhu, Hong, Chen, Hongbo, Mayo, Lior, Geng, Jiefei, Amin, Palak, DeWitt, Judy Park, Mookhtiar, Adnan Kasim, Florez, Marcus, Ouchida, Amanda Tomie, Fan, Jian-bing, Pasparakis, Manolis, Kelliher, Michelle A., Ravits, John, Yuan, Junying·2016·Science

DOI 10.1126/science.aaf6803PMC PMC5444917

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Abstract

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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Additional file 8 of Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
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Additional file 3 of Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
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Additional file 7 of Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
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Additional file 5 of Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
Dong, Y., Yu, H., Li, X., Bian, K., Zheng, Y., Dai, M., Feng, X., Sun, Y., He, Y., Yu, B., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20495842
Additional file 2 of Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
Dong, Y., Yu, H., Li, X., Bian, K., Zheng, Y., Dai, M., Feng, X., Sun, Y., He, Y., Yu, B., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20495833
Additional file 1 of Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer’s disease
Agujetas, V. R., Barbero-Camps, E., de Dios, C., Podlesniy, P., Abadin, X., Morales, A., Marı́, M., Trullás, R., & Colell, A. (2021) · Figshare · doi:10.6084/m9.figshare.14183579
Additional file 9 of Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
Dong, Y., Yu, H., Li, X., Bian, K., Zheng, Y., Dai, M., Feng, X., Sun, Y., He, Y., Yu, B., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20495857
Additional file 1 of Stressor control and regional inflammatory responses in the brain: regulation by the basolateral amygdala
Adkins, A. M., Colby, E. M., Kim, W.-K., Wellman, L. L., & Sanford, L. D. (2024) · Figshare · doi:10.6084/m9.figshare.26592398
Additional file 6 of Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
Dong, Y., Yu, H., Li, X., Bian, K., Zheng, Y., Dai, M., Feng, X., Sun, Y., He, Y., Yu, B., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20495848
Additional file 1 of Quantitative patterns of motor cortex proteinopathy across ALS genotypes
Nolan, M., Scott, C., Gamarallage, M. P., Lunn, D., Carpenter, K., McDonough, E., Meyer, D. E., Kaanumalle, S., Santamaria-Pang, A., Turner, M. R., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12607271
Additional file 1 of Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
Dong, Y., Yu, H., Li, X., Bian, K., Zheng, Y., Dai, M., Feng, X., Sun, Y., He, Y., Yu, B., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20495830
Additional file 4 of Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
Dong, Y., Yu, H., Li, X., Bian, K., Zheng, Y., Dai, M., Feng, X., Sun, Y., He, Y., Yu, B., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20495839
Amyotrophic lateral sclerosis: Neural repair strategies based on multi-target synchronous interventions
Liu, J., Zhou, L., Deng, Y., & Xu, R. (2026) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00221 · Cited by 1
Current Trends in Biomarkers and Diagnosis of Prevalent Neurological Infectious Diseases
Verma, K., Priyanka, Singh, S., & Yadav, N. (2026) · IGI Global eBooks · doi:10.4018/979-8-3693-4070-7.ch007
A Narrative Review of Necroptosis in Neuromuscular Junction Disorders: Pathogenesis and Therapeutic Strategies
Qaisar, R., & Deepa, S. S. (2026) · Archives of Medical Research · doi:10.1016/j.arcmed.2026.103401
Spinal motor neuron degeneration after brachial plexus avulsion: mechanisms and therapeutic targets
Yang, J., Qin, B., Yang, Y., Fang, J., & He, W. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1778229
When optineurin meets innate immunity
Zhang, L., Han, J., Yang, Z., Xue, M., & Zheng, C. (2026) · Academia Immunity and Disease · doi:10.20935/acadimmunodis8165
Sarsasapogenin ameliorates Alzheimer's disease by dual inhibition of RIPK1-mediated necroptosis and pyroptosis
Guo, Y., Li, X., Chen, Y., Li, Y., Cheng, Q., Jiang, Y., Tian, S., Yuan, B., Liu, Y., Hu, H., et al. (2026) · Cellular Signalling · doi:10.1016/j.cellsig.2026.112481
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GENG, L., Pan, J., & Li, J. (2026) · Scientia Sinica Vitae · doi:10.1360/ssv-2025-0282
Natural Products Inhibiting Necroptosis: Molecular Mechanisms and Therapeutic Opportunities
Yang, S., Shi, Y., Liu, T., Meng, X., & Shen, X. (2026) · Journal of Visualized Experiments · doi:10.3791/70315
Machine learning and molecular simulation-based discovery of novel RIPK1 inhibitors
Hasan, M. M., Shill, M. C., Bepari, A. K., Reza, H. M., & Hossain, M. (2026) · In Silico Pharmacology · doi:10.1007/s40203-026-00586-8
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Xi, R., Zheng, X., Zhao, J., & Fu, Y. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03819-x · Cited by 1
“It triggers cytoplasmic translocation and pathological aggregation of TDP-43 in neighboring neurons, ultimately leading to neuronal loss and motor dysfunction [124].”
Probing Allosteric Kinase Modulators as Next Game-Changers in Fighting Neurodegeneration
Roggiolani, E., Rosini, M., Minarini, A., & Basagni, F. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c03783
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Koppinen, T. K., Takacs, L., Collin, L., Mracsko, E. Z., & Keaney, J. (2026) · Glial health research. · doi:10.1016/j.ghres.2026.100015
NR_045396/MicroRNA761/FADD axis regulates necroptosis and survival of retinal ganglion cells
Tian, K., Duan, X., Chen, B., Wang, C., Jiang, Q., Ren, Y., 蔡秉翰, Ma, B., Yang, J., Ye, C., et al. (2026) · Experimental Eye Research · doi:10.1016/j.exer.2026.111135
Új megközelítés egy feltörekvő neurodegenerációs célpont kutatásában
Petró, J. L., Hornyánszky, G., & Éles, J. (2026) · Scientia et Securitas · doi:10.1556/112.2026.00313
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Receptor-interacting protein kinase 1 regulates microglial polarization via the Csf3-JAK2/STAT3 axis in lipopolysaccharide-induced inflammation and lysolecithin-induced demyelination
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LXR Pathway Activation by T0901317: A Novel Potential Experimental Strategy for ALS-Related Cognitive and Motor Impairments via Suppression of Necroptosis-associated RIPK1/RIPK3/MLKL Markers
Zhang, X., Zhang, L., Chen, L., Yu, W., Zhao, Y., 黄银辉, & Xu, Z. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-06106-1
“[5, 15], In contrast, Baris et al. found that inactivation of RIPK1 does not ameliorate the decline of muscle strength and nerve function in the SOD1 mouse model[16].”
Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets
Li, T., Zhang, Q., Wu, Y., & Huang, R. (2026) · MedComm · doi:10.1002/mco2.70915
“In optineurin deficient models, enhanced RIPK1 signaling drives progressive dysmyelination and axonal degeneration and activates necroptosis-related machinery in the CNS, linking RIPK1 activation to neuronal injury and inflammatory disease amplification [ 40 ].”
Spatiotemporal Dynamics and Cellular States of Neuroinflammation in Amyotrophic Lateral Sclerosis: Implications for Stage‑Specific Therapeutics
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“Mutations in ALS-linked genes such as TBK1 [155] and OPTN [156] impair this regulation, leading to excessive RIPK1 kinase activity in experimental models.”
Thymosin Alpha‐1 Provides Direct Neuroprotection by Engaging the Orexin Receptor HCRTR1 to Suppress Neuronal Necroptosis
Kang, X., Wang, S., Zhang, L., Hu, M., Su, X., Liu, Y., Qin, Q., Yi, H., Yuan, L., Cai, W., et al. (2026) · Advanced Science · doi:10.1002/advs.202522372
“Mechanistically, our work positions RIPK3-mediated necroptosis, a major driver of inflammation and cell death in stroke and other neurodegenerative conditions [ 14, 17, 25–29 ], as a key downstream target of the T α 1-HCRTR1 axis.”
HIMALAYA: learning from another negative phase 2 trial in ALS
Hardiman, O. M. (2026) · The Lancet Neurology · doi:10.1016/s1474-4422(26)00318-2

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: Ito, Yasushi
Ofengeim, Dimitry
Najafov, Ayaz
Das, Sudeshna
Li, Ying
Zhu, Hong
Chen, Hongbo
Mayo, Lior
Amin, Palak
Mookhtiar, Adnan Kasim
Florez, Marcus
Fan, Jian-bing
Pasparakis, Manolis
Kelliher, Michelle A.
Ravits, John
Yuan, Junying
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2016-08-05
Volume: 353
Issue: 6299
Pages: 603-608
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.aaf6803
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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RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

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