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 - 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
U2 - 10.1126/science.aaf6803
DO - 10.1126/science.aaf6803
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AN - SCOPUS:84982851750
SN - 0036-8075
VL - 353
SP - 603
EP - 608
JO - Science
JF - Science
IS - 6299
ER -