For Motor Neurons To Survive, NEK1 May Be On The Line

A new study may provide insight into why some people may be at increased risk of developing ALS. The report, led by Harvard Medical School’s Junying Yuan in Boston, Massachusetts, found that NEK1 kinase may help regulate RIP1 kinase by blocking its ability to trigger necroptosis (Amin et al., 2018). The results suggest that key changes in NEK1 may make motor neurons more vulnerable to the disease.

One word: necroptosis. Motor neurons may degenerate in ALS due to necroptosis through a RIP1 kinase-mediated mechanism. This programmed form of necrosis (b) is distinct from apoptosis (a) because the plasma membrane loses integrity early, and organelles including mitochondria swell up instead of fragment [Courtesy of Vandenabeele et al., 2010, Nature Reviews Molecular Cell Biology].

The findings build on previous studies from Project MinE, led by University of Massachusetts Medical School’s John Landers and UMC Utrecht’s Jan Veldink in the Netherlands, which found that variants in the NEK1 gene increase the susceptibility of developing ALS (see August 2016 news; Kenna et al., 2016).

The study appeared on June 26 in the Proceedings of the National Academy of Sciences.

RIP1 kinase may contribute to ALS by promoting inflammation and axonal loss (see September 2016 news; Ito et al., 2016). Scientists at Denali Therapeutics in San Francisco, California are therefore developing potential therapies, including DNL747, which block this enzyme in hopes to protect motor neurons against the disease (see February 2017 news).

The approach aims in part to block necroptosis, a programmed form of necrosis, which may destroy motor neurons in the disease (see Feb 2014 news; Re et al., 2014; Degterev et al., 2008).

DNL747 is emerging as a key alternative to GlaxoSmithKline’s GSK2982772, due to its ability, according to Denali Therapeutics, to be delivered to the brain (see Harris et al., 2017).

A phase 1 clinical trial in the Netherlands is ongoing. The “first-in-man” study launched in March 2018. Stay tuned.

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To learn more about the emerging role of RIPK1 in neurodegenerative diseases, check out Targeting RIPK1 May Increase Granularity in FTD.

Featured Paper

Amin P, Florez M, Najafov A, Pan H, Geng J, Ofengeim D, Dziedzic SA, Wang H, Barrett VJ, Ito Y, LaVoie MJ, Yuan J. Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis. Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E5944-E5953. [PubMed].

References

Kenna KP, van Doormaal PT, Dekker AM, Ticozzi N, Kenna BJ, Diekstra FP, van Rheenen W, van Eijk KR, Jones AR, Keagle P, Shatunov A, Sproviero W, Smith BN, van Es MA, Topp SD, Kenna A, Miller JW, Fallini C, Tiloca C, McLaughlin RL, Vance C, Troakes C, Colombrita C, Mora G, Calvo A, Verde F, Al-Sarraj S, King A, Calini D, de Belleroche J, Baas F, van der Kooi AJ, de Visser M, Ten Asbroek AL, Sapp PC, McKenna-Yasek D, Polak M, Asress S, Muñoz-Blanco JL, Strom TM, Meitinger T, Morrison KE; SLAGEN Consortium, Lauria G, Williams KL, Leigh PN, Nicholson GA, Blair IP, Leblond CS, Dion PA, Rouleau GA, Pall H, Shaw PJ, Turner MR, Talbot K, Taroni F, Boylan KB, Van Blitterswijk M, Rademakers R, Esteban-Pérez J, García-Redondo A, Van Damme P, Robberecht W, Chio A, Gellera C, Drepper C, Sendtner M, Ratti A, Glass JD, Mora JS, Basak NA, Hardiman O, Ludolph AC, Andersen PM, Weishaupt JH, Brown RH Jr, Al-Chalabi A, Silani V, Shaw CE, van den Berg LH, Veldink JH, Landers JE. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat Genet. 2016 Sep;48(9):1037-42. [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].

Harris PA, Berger SB, Jeong JU, Nagilla R, Bandyopadhyay D, Campobasso N, Capriotti CA, Cox JA, Dare L, Dong X, Eidam PM, Finger JN, Hoffman SJ, Kang J, Kasparcova V, King BW, Lehr R, Lan Y, Leister LK, Lich JD, MacDonald TT, Miller NA, Ouellette MT, Pao CS, Rahman A, Reilly MA, Rendina AR, Rivera EJ, Schaeffer MC, Sehon CA, Singhaus RR, Sun HH, Swift BA, Totoritis RD, Vossenkämper A, Ward P, Wisnoski DD, Zhang D, Marquis RW, Gough PJ, Bertin J. Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases. J Med Chem. 2017 Feb 23;60(4):1247-1261. [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

Weinlich R, Oberst A, Beere HM, Green DR. Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol. 2017 Feb;18(2):127-136. [PubMed].

Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010 Oct;11(10):700-14. doi: 10.1038/nrm2970. Epub 2010 Sep 8. [PubMed].

For people with ALS and their families, learn more about NEK1 by checking out this FAQ.

 

Denali disease-als DNL747 GlaxoSmithKline GSK2982772 RIP1 kinase topic-preclinical topic-randd
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