RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

被引：564

作者：

Ito, Yasushi ^{[1
]}

Ofengeim, Dimitry ^{[1
]}

Najafov, Ayaz ^{[1
]}

Das, Sudeshna ^{[2
]}

Saberi, Shahram ^{[3
,4
]}

Li, Ying ^{[1
,5
]}

Hitomi, Junichi ^{[1
]}

Zhu, Hong ^{[1
]}

Chen, Hongbo ^{[1
]}

Mayo, Lior ^{[6
]}

Geng, Jiefei ^{[1
]}

Amin, Palak ^{[1
]}

DeWitt, Judy Park ^{[1
]}

Mookhtiar, Adnan Kasim ^{[1
]}

Florez, Marcus ^{[1
]}

Ouchida, Amanda Tomie ^{[1
]}

Fan, Jian-bing ^{[7
]}

Pasparakis, Manolis ^{[8
]}

Kelliher, Michelle A. ^{[9
]}

Ravits, John ^{[3
,4
]}

Yuan, Junying ^{[1
,5
]}

机构：

[1] Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA

[2] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Cambridge, MA 02139 USA

[3] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA

[4] Univ Calif San Diego, Dept Neurosci, ALS Translat Res Program, La Jolla, CA 92093 USA

[5] Chinese Acad Sci, Shanghai Inst Organ Chem, Interdisciplinary Res Ctr Biol & Chem, 26 QiuYue Rd, Shanghai 201210, Peoples R China

[6] Harvard Med Sch, Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA

[7] Illumina Inc, San Diego, CA 92122 USA

[8] Univ Cologne, Inst Genet, D-50674 Cologne, Germany

[9] Univ Massachusetts, Dept Canc Biol, Sch Med, Worcester, MA 01605 USA

来源：

SCIENCE | 2016年 / 353卷 / 6299期

基金：

日本学术振兴会; 欧洲研究理事会;

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; KAPPA-B ACTIVATION; MOTOR-NEURON DEATH; CELL-DEATH; SELF-DESTRUCTION; OPTINEURIN; KINASE; IDENTIFICATION; MICE; REGENERATION;

D O I：

10.1126/science.aaf6803

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：603 / 608

页数：6

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