Universität zu Köln

Ito, Yasushi, Ofengeim, Dimitry, Najafov, Ayaz ORCID: 0000-0002-1350-2056, Das, Sudeshna ORCID: 0000-0002-9486-6811, Saberi, Shahram, Li, Ying, Hitomi, Junichi, Zhu, Hong ORCID: 0000-0002-2575-4031, Chen, Hongbo ORCID: 0000-0002-9084-7277, Mayo, Lior ORCID: 0000-0002-1296-6692, Geng, Jiefei, Amin, Palak ORCID: 0000-0001-5617-8703, DeWitt, Judy Park, Mookhtiar, Adnan Kasim, Florez, Marcus, Ouchida, Amanda Tomie, Fan, Jian-bing, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Kelliher, Michelle A., Ravits, John and Yuan, Junying (2016). RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science, 353 (6299). S. 603 - 609. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1095-9203

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ito, Yasushi UNSPECIFIED UNSPECIFIED UNSPECIFIED Ofengeim, Dimitry UNSPECIFIED UNSPECIFIED UNSPECIFIED Najafov, Ayaz UNSPECIFIED orcid.org/0000-0002-1350-2056 UNSPECIFIED Das, Sudeshna UNSPECIFIED orcid.org/0000-0002-9486-6811 UNSPECIFIED Saberi, Shahram UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Ying UNSPECIFIED UNSPECIFIED UNSPECIFIED Hitomi, Junichi UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhu, Hong UNSPECIFIED orcid.org/0000-0002-2575-4031 UNSPECIFIED Chen, Hongbo UNSPECIFIED orcid.org/0000-0002-9084-7277 UNSPECIFIED Mayo, Lior UNSPECIFIED orcid.org/0000-0002-1296-6692 UNSPECIFIED Geng, Jiefei UNSPECIFIED UNSPECIFIED UNSPECIFIED Amin, Palak UNSPECIFIED orcid.org/0000-0001-5617-8703 UNSPECIFIED DeWitt, Judy Park UNSPECIFIED UNSPECIFIED UNSPECIFIED Mookhtiar, Adnan Kasim UNSPECIFIED UNSPECIFIED UNSPECIFIED Florez, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Ouchida, Amanda Tomie UNSPECIFIED UNSPECIFIED UNSPECIFIED Fan, Jian-bing UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Kelliher, Michelle A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ravits, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Yuan, Junying UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-266788
DOI:	10.1126/science.aaf6803
Journal or Publication Title:	Science
Volume:	353
Number:	6299
Page Range:	S. 603 - 609
Date:	2016
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication:	WASHINGTON
ISSN:	1095-9203
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AMYOTROPHIC-LATERAL-SCLEROSIS; KAPPA-B ACTIVATION; MOTOR-NEURON DEATH; CELL-DEATH; SELF-DESTRUCTION; OPTINEURIN; KINASE; IDENTIFICATION; MICE; REGENERATION Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26678