Protein Kinase CK2 and Its Potential Role As a Therapeutic Target in Huntington's Disease

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2022 Aug 26

PMID 36009526

Authors

Angel White

Anna McGlone

Rocio Gomez-Pastor

Affiliations

Soon will be listed here.

Abstract

Huntington's Disease (HD) is a devastating neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the gene, for which no disease modifying therapies are currently available. Much of the recent research has focused on developing therapies to directly lower HTT expression, and while promising, these therapies have presented several challenges regarding administration and efficacy. Another promising therapeutic approach is the modulation of HTT post-translational modifications (PTMs) that are dysregulated in disease and have shown to play a key role in HTT toxicity. Among all PTMs, modulation of HTT phosphorylation has been proposed as an attractive therapeutic option due to the possibility of orally administering specific kinase effectors. One of the kinases described to participate in HTT phosphorylation is Protein Kinase CK2. CK2 has recently emerged as a target for the treatment of several neurological and psychiatric disorders, although its role in HD remains controversial. While pharmacological studies in vitro inhibiting CK2 resulted in reduced HTT phosphorylation and increased toxicity, genetic approaches in mouse models of HD have provided beneficial effects. In this review we discuss potential therapeutic approaches related to the manipulation of HTT-PTMs with special emphasis on the role of CK2 as a therapeutic target in HD.

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References

Vitet H, Brandt V, Saudou F . Traffic signaling: new functions of huntingtin and axonal transport in neurological disease. Curr Opin Neurobiol. 2020; 63:122-130. DOI: 10.1016/j.conb.2020.04.001. View

Yu D, Zarate N, White A, Coates D, Tsai W, Nanclares C . CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in huntington's disease. Acta Neuropathol Commun. 2022; 10(1):83. PMC: 9164558. DOI: 10.1186/s40478-022-01379-8. View

Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg M . alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002; 4(2):160-4. DOI: 10.1038/ncb748. View

Watkin E, Arbez N, Waldron-Roby E, OMeally R, Ratovitski T, Cole R . Phosphorylation of mutant huntingtin at serine 116 modulates neuronal toxicity. PLoS One. 2014; 9(2):e88284. PMC: 3914950. DOI: 10.1371/journal.pone.0088284. View

Singh N, Ramji D . Protein kinase CK2, an important regulator of the inflammatory response?. J Mol Med (Berl). 2008; 86(8):887-97. DOI: 10.1007/s00109-008-0352-0. View

Ratovitski T, Jiang M, OMeally R, Rauniyar P, Chighladze E, Farago A . Interaction of huntingtin with PRMTs and its subsequent arginine methylation affects HTT solubility, phase transition behavior and neuronal toxicity. Hum Mol Genet. 2021; 31(10):1651-1672. PMC: 9122652. DOI: 10.1093/hmg/ddab351. View

Sathasivam K, Neueder A, Gipson T, Landles C, Benjamin A, Bondulich M . Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc Natl Acad Sci U S A. 2013; 110(6):2366-70. PMC: 3568346. DOI: 10.1073/pnas.1221891110. View

Yao J, Ong S, Bajjalieh S . Huntingtin is associated with cytomatrix proteins at the presynaptic terminal. Mol Cell Neurosci. 2014; 63:96-100. DOI: 10.1016/j.mcn.2014.10.003. View

Lou D, Dominguez I, Toselli P, Landesman-Bollag E, OBrien C, Seldin D . The alpha catalytic subunit of protein kinase CK2 is required for mouse embryonic development. Mol Cell Biol. 2007; 28(1):131-9. PMC: 2223292. DOI: 10.1128/MCB.01119-07. View

10.

Kawada T . Risk reduction of Parkinson disease by statin therapy in patients with diabetes. Ann Neurol. 2016; 81(1):157. DOI: 10.1002/ana.24809. View

11.

van Vugt J, Siesling S, Vergeer M, van der Velde E, Roos R . Clozapine versus placebo in Huntington's disease: a double blind randomised comparative study. J Neurol Neurosurg Psychiatry. 1997; 63(1):35-9. PMC: 2169648. DOI: 10.1136/jnnp.63.1.35. View

12.

Benn C, Sun T, Sadri-Vakili G, McFarland K, DiRocco D, Yohrling G . Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J Neurosci. 2008; 28(42):10720-33. PMC: 2586288. DOI: 10.1523/JNEUROSCI.2126-08.2008. View

13.

Chafekar S, Duennwald M . Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin. PLoS One. 2012; 7(5):e37929. PMC: 3359295. DOI: 10.1371/journal.pone.0037929. View

14.

Coppen E, Roos R . Current Pharmacological Approaches to Reduce Chorea in Huntington's Disease. Drugs. 2016; 77(1):29-46. PMC: 5216093. DOI: 10.1007/s40265-016-0670-4. View

15.

Marshall C, McBride J, Changolkar L, Riddle D, Trojanowski J, Lee V . Inhibition of CK2 mitigates Alzheimer's tau pathology by preventing NR2B synaptic mislocalization. Acta Neuropathol Commun. 2022; 10(1):30. PMC: 8895919. DOI: 10.1186/s40478-022-01331-w. View

16.

Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, OBrien S . CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 2010; 70(24):10288-98. DOI: 10.1158/0008-5472.CAN-10-1893. View

17.

Li H, Yeh P, Chiu H, Tang C, Tu B . Hyperphosphorylation as a defense mechanism to reduce TDP-43 aggregation. PLoS One. 2011; 6(8):e23075. PMC: 3151276. DOI: 10.1371/journal.pone.0023075. View

18.

Alessi D, Caudwell F, Andjelkovic M, Hemmings B, Cohen P . Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 1996; 399(3):333-8. DOI: 10.1016/s0014-5793(96)01370-1. View

19.

Gomez-Pastor R, Burchfiel E, Thiele D . Regulation of heat shock transcription factors and their roles in physiology and disease. Nat Rev Mol Cell Biol. 2017; 19(1):4-19. PMC: 5794010. DOI: 10.1038/nrm.2017.73. View

20.

Battistutta R, Sarno S, De Moliner E, Papinutto E, Zanotti G, Pinna L . The replacement of ATP by the competitive inhibitor emodin induces conformational modifications in the catalytic site of protein kinase CK2. J Biol Chem. 2000; 275(38):29618-22. DOI: 10.1074/jbc.M004257200. View