Targeting RIPK1 May Increase Granularity in FTD

Mechanism stat. Treatment with RIP1 kinase inhibitor necrostatin-1s did not significantly increase progranulin levels in vitro suggesting that blocking this activity is unlikely to be therapeutically beneficial in PGRN-linked FTD. [(Takahashi et al., 2012) under CC-BY-NC 4.0 license.]

Receptor Interacting Serine/Threonine Protein Kinase 1 (RIPK1) regulates levels of the secreted growth factor progranulin (PGRN) according to a study published on January 9 in the Journal of Biological Chemistry. The study, led by Steve Finkbeiner of the Gladstone Institutes in San Francisco, found that reduction of RIPK1 by siRNA knockdown in primary cortical neurons from haploinsufficient PGRN FTD mice increased progranulin levels by nearly 2-fold. The regulation appeared to be kinase-independent and at the translational level. The researchers discovered the protein by screening the murine kinome for regulators of progranulin in vitro. The results suggest that targeting RIPK1 may be a potential strategy to treat PGRN-linked FTD.

Target: ALS

Researchers first suspected that RIPK1 might play a key role in neurodegenerative diseases by studying models of ALS. Reporting in 2016, a research team led by Junying Yuan of Harvard Medical School found that RIPK1 appeared to promote inflammation and glial dysfunction in motor neurons of a SOD1 and a OPTN mouse model of ALS (see September 2016 news; Ito et al., 2016). What’s more, RIPK1 appeared to mediate the degeneration of these motor neurons by triggering necroptosis through a kinase-based mechanism. The results came at the heels of a 2014 in vitro stem cell-based study led by Columbia University’s Serge Przedborski in New York that fingered necroptosis as a key mechanism that might destroy motor neurons in sporadic and familial ALS (see February 2014 news; Re et al., 2014).

Together, the results suggest that blocking RIPK1 kinase might be a potential therapeutic strategy for ALS. The strategy is currently being developed by Denali Therapeutics in San Francisco as a potential treatment for ALS and Alzheimer’s disease (see September 2016 news). A phase 1 clinical trial involving healthy volunteers in Europe is planned.

References:

Mason AR, Elia LP, Finkbeiner S. The Receptor-Interacting Serine/Threonine Protein Kinase 1 (Ripk1) Regulates Progranulin Levels. J Biol Chem. 2017 Jan 9. pii: jbc.M116.752006. [PubMed]

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. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science. 2016 Aug 5;353(6299):603-8.[PubMed].

Re DB, Le Verche V, Yu C, Amoroso MW, Politi KA, Phani S, Ikiz B, Hoffmann L, Koolen M, Nagata T, Papadimitriou D, Nagy P, Mitsumoto H, Kariya S, Wichterle H, Henderson CE, Przedborski S. Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron. 2014 Mar 5;81(5):1001-8. [PubMed].

Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008 May;4(5):313-21. [PubMed]

Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005 Jul;1(2):112-9. [PubMed].

Further reading:

Najjar M, Saleh D, Zelic M, Nogusa S, Shah S, Tai A, Finger JN, Polykratis A, Gough PJ, Bertin J, Whalen MJ, Pasparakis M, Balachandran S, Kelliher M, Poltorak A, Degterev A. RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4. Immunity. 2016 Jul 19;45(1):46-59. [PubMed].

Najjar M, Suebsuwong C, Ray SS, Thapa RJ, Maki JL, Nogusa S, Shah S, Saleh D, Gough PJ, Bertin J, Yuan J, Balachandran S, Cuny GD, Degterev A. Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. Cell Rep. 2015 Mar 24;10(11):1850-60. [PubMed].

Image on the home page: Crystal structure of RIPK1 kinase. RCSB/PDB.

disease-ftd OPTN RIP1 SOD1 topic-preclinical
Share this:
Facebooktwittergoogle_plusmailFacebooktwittergoogle_plusmail