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Science. 2016 Aug 5;353(6299):603-8. doi: 10.1126/science.aaf6803.

RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS.

Author information

1
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
2
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Cambridge, MA 02139, USA.
3
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.
4
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.
5
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
6
Illumina, Inc., San Diego, CA 92122, USA.
7
Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
8
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
9
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.

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.

PMID:
27493188
PMCID:
PMC5444917
DOI:
10.1126/science.aaf6803
[Indexed for MEDLINE]
Free PMC Article

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