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 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.
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Yasushi
authors: Y
authors: Ito
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Dimitry
authors: D
authors: Ofengeim
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Ayaz
authors: A
authors: Najafov
authors: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Cambridge, MA 02139, USA.
authors: Sudeshna
authors: S
authors: Das
authors: Department of Neurology, Harvard Medical School, Boston, MA 02115, USA. ALS Translational Research Program, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Shahram
authors: S
authors: Saberi
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 QiuYue Road, PuDong District, Shanghai, 201210, China.
authors: Ying
authors: Y
authors: Li
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Junichi
authors: J
authors: Hitomi
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Hong
authors: H
authors: Zhu
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Hongbo
authors: H
authors: Chen
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Lior
authors: L
authors: Mayo
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Jiefei
authors: J
authors: Geng
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Palak
authors: P
authors: Amin
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Judy Park
authors: JP
authors: DeWitt
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Adnan Kasim
authors: AK
authors: Mookhtiar
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Marcus
authors: M
authors: Florez
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors: Amanda Tomie
authors: AT
authors: Ouchida
authors: Illumina, Inc., San Diego, CA 92122, USA.
authors: Jian-bing
authors: JB
authors: Fan
authors: Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
authors: Manolis
authors: M
authors: Pasparakis
authors: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors: Michelle A
authors: MA
authors: Kelliher
authors: Department of Neurology, Harvard Medical School, Boston, MA 02115, USA. ALS Translational Research Program, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: John
authors: J
authors: Ravits
authors: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 QiuYue Road, PuDong District, Shanghai, 201210, China. jyuan@hms.harvard.edu.
authors: Junying
authors: J
authors: Yuan
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001369:Axons / Q000473:pathology*; D018797:Cell Cycle Proteins; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D026901:Membrane Transport Proteins; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D009410:Nerve Degeneration / Q000235:genetics*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013489:Suppression, Genetic; D035582:Transcription Factor TFIIIA / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; C000606290:SOD1 protein, human; D035582:Transcription Factor TFIIIA; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases