RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

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

doi:10.1126/science.aaf6803

RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

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

Research output: Contribution to journal › Article › peer-review

393 Scopus citations

Abstract

Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1^G93A transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.

Original language	English (US)
Pages (from-to)	603-608
Number of pages	6
Journal	Science
Volume	353
Issue number	6299
DOIs	https://doi.org/10.1126/science.aaf6803
State	Published - Aug 5 2016
Externally published	Yes

ASJC Scopus subject areas

General

Access to Document

10.1126/science.aaf6803

Cite this

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., ... Yuan, J. (2016). RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science, 353(6299), 603-608. https://doi.org/10.1126/science.aaf6803

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, JP, Mookhtiar, AK, Florez, M, Ouchida, AT, Fan, JB, Pasparakis, M, Kelliher, MA, Ravits, J & Yuan, J 2016, 'RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS', Science, vol. 353, no. 6299, pp. 603-608. https://doi.org/10.1126/science.aaf6803

@article{2ce402ac257048478080f0970fa2cc7d,

title = "RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS",

abstract = "Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.",

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

note = "Funding Information: We thank B. Caldarone of the NeuroBehavior Laboratory, Harvard Institute of Medicine, for conducting mouse behavior analysis; J. Walters at the Harvard Medical School Nikon microscope facility for fluorescence microscopy; and M. Ericsson of the Electron Microscopy Facility at Harvard Medical School for analysis. This work was supported in part by grants from the National Institute of Neurological Disorders and Stroke (1R01NS082257) and the National Institute on Aging (1R01AG047231), NIH; and by the National Science and Technology Major Project of China (2014ZX09102001-002) and State Key Program of National Natural Science of China (no. 31530041) (to J.Y.); National Institute of Allergy and Infectious Diseases (2RO1AI075118) (to M.A.K.); European Research Council Advanced Grants (grant agreement no. 323040) (to M.P.) and Target ALS (to J.R.). Y.I. was supported in part by postdoctoral fellowships from Japan (Daiichi Sankyo Foundation of Life Science, The Nakatomi Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Japan Society for the Promotion of Science). D.O. was supported by a postdoctoral fellowship from the National Multiple Sclerosis Society and a National Multiple Sclerosis Society Career Transition Award. H.C. was supported by a grant from Huazhong University of Science and Technology, Wuhan, China. Ripk3-/- mice and K48 ubiquitin antibodies are available from V. Dixit under a material transfer agreement with Genentech. Ripk1D138N mice are available from M. Pasparakis of University of Cologne, Germany, under a material transfer agreement with University of Cologne. J.Y. is an inventor on U.S. patent 7,491,743 B2 held by Harvard University that covers 7-Cl-O-Nec-1. Publisher Copyright: {\textcopyright} 2016 by The American Society for Biochemistry and Molecular Biology, Inc.",

year = "2016",

month = aug,

day = "5",

doi = "10.1126/science.aaf6803",

language = "English (US)",

volume = "353",

pages = "603--608",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6299",

}

TY - JOUR

T1 - RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

AU - Ito, Yasushi

AU - Ofengeim, Dimitry

AU - Najafov, Ayaz

AU - Das, Sudeshna

AU - Saberi, Shahram

AU - Li, Ying

AU - Hitomi, Junichi

AU - Zhu, Hong

AU - Chen, Hongbo

AU - Mayo, Lior

AU - Geng, Jiefei

AU - Amin, Palak

AU - DeWitt, Judy Park

AU - Mookhtiar, Adnan Kasim

AU - Florez, Marcus

AU - Ouchida, Amanda Tomie

AU - Fan, Jian Bing

AU - Pasparakis, Manolis

AU - Kelliher, Michelle A.

AU - Ravits, John

AU - Yuan, Junying

N1 - Funding Information: We thank B. Caldarone of the NeuroBehavior Laboratory, Harvard Institute of Medicine, for conducting mouse behavior analysis; J. Walters at the Harvard Medical School Nikon microscope facility for fluorescence microscopy; and M. Ericsson of the Electron Microscopy Facility at Harvard Medical School for analysis. This work was supported in part by grants from the National Institute of Neurological Disorders and Stroke (1R01NS082257) and the National Institute on Aging (1R01AG047231), NIH; and by the National Science and Technology Major Project of China (2014ZX09102001-002) and State Key Program of National Natural Science of China (no. 31530041) (to J.Y.); National Institute of Allergy and Infectious Diseases (2RO1AI075118) (to M.A.K.); European Research Council Advanced Grants (grant agreement no. 323040) (to M.P.) and Target ALS (to J.R.). Y.I. was supported in part by postdoctoral fellowships from Japan (Daiichi Sankyo Foundation of Life Science, The Nakatomi Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Japan Society for the Promotion of Science). D.O. was supported by a postdoctoral fellowship from the National Multiple Sclerosis Society and a National Multiple Sclerosis Society Career Transition Award. H.C. was supported by a grant from Huazhong University of Science and Technology, Wuhan, China. Ripk3-/- mice and K48 ubiquitin antibodies are available from V. Dixit under a material transfer agreement with Genentech. Ripk1D138N mice are available from M. Pasparakis of University of Cologne, Germany, under a material transfer agreement with University of Cologne. J.Y. is an inventor on U.S. patent 7,491,743 B2 held by Harvard University that covers 7-Cl-O-Nec-1. Publisher Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2016/8/5

Y1 - 2016/8/5

N2 - Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.

AB - Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.

UR - http://www.scopus.com/inward/record.url?scp=84982851750&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982851750&partnerID=8YFLogxK

U2 - 10.1126/science.aaf6803

DO - 10.1126/science.aaf6803

M3 - Article

C2 - 27493188

AN - SCOPUS:84982851750

SN - 0036-8075

VL - 353

SP - 603

EP - 608

JO - Science

JF - Science

IS - 6299

ER -

RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this