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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Science 2016 ; 353 (6299): 603-8 Nephropedia Template TP
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RIPK1 Mediates Axonal Degeneration By Promoting Inflammation and Necroptosis in ALS #MMPMID27493188
Ito Y; Ofengeim D; Najafov A; Das S; Saberi S; Li Y; Hitomi J; Zhu H; Chen H; Mayo L; Geng J; Amin P; DeWitt JP; Mookhtiar AK; Florez M; Ouchida AT; Fan Jb; Pasparakis M; Kelliher MA; Ravits J; Yuan J
Science 2016[Aug]; 353 (6299): 603-8 PMID27493188show ga
Mutations in 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 is unclear. Here, we found that optineurin actively suppressed RIPK1-dependent signaling by regulating its turnover. Loss-of-OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery, including RIPK1, RIPK3 and MLKL, in the CNS. Furthermore, RIPK1/RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS. Thus, RIPK1/RIPK3 plays a critical role in mediating progressive axonal degeneration and inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.