N6-Furfuryladenine is Protective in Huntington's Disease Models by Signaling Huntingtin Phosphorylation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Jul 11

PMID 29987005

Citations 21

Authors

Laura E Bowie

Tamara Maiuri

Melanie Alpaugh

Michelle Gabriel

Nicolas Arbez

Danny Galleguillos

Claudia L K Hung

Shreya Patel

Jianrun Xia

Nicholas T Hertz

Christopher A Ross

David W Litchfield

Simonetta Sipione

Ray Truant

Affiliations

Soon will be listed here.

Abstract

The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington's disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA adducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.

Citing Articles

The N17 domain of huntingtin as a multifaceted player in Huntington's disease.

Cho H Front Mol Biosci. 2025; 11():1527313.

PMID: 39845903 PMC: 11753208. DOI: 10.3389/fmolb.2024.1527313.

Protein modification in neurodegenerative diseases.

Ramazi S, Dadzadi M, Darvazi M, Seddigh N, Allahverdi A MedComm (2020). 2024; 5(8):e674.

PMID: 39105197 PMC: 11298556. DOI: 10.1002/mco2.674.

Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases.

Li W, Li H, Wang J, Liu R, Wang X Cell Biosci. 2024; 14(1):22.

PMID: 38347638 PMC: 10863199. DOI: 10.1186/s13578-023-01189-y.

IKBKB reduces huntingtin aggregation by phosphorylating serine 13 via a non-canonical IKK pathway.

Cariulo C, Martufi P, Verani M, Toledo-Sherman L, Lee R, Dominguez C Life Sci Alliance. 2023; 6(10).

PMID: 37553253 PMC: 10410066. DOI: 10.26508/lsa.202302006.

Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases.

Shadfar S, Parakh S, Jamali M, Atkin J Transl Neurodegener. 2023; 12(1):18.

PMID: 37055865 PMC: 10103468. DOI: 10.1186/s40035-023-00350-4.

References

Gu X, Cantle J, Greiner E, Lee C, Barth A, Gao F . N17 Modifies mutant Huntingtin nuclear pathogenesis and severity of disease in HD BAC transgenic mice. Neuron. 2015; 85(4):726-41. PMC: 4386927. DOI: 10.1016/j.neuron.2015.01.008. View

Sorrentino V, Romani M, Mouchiroud L, Beck J, Zhang H, DAmico D . Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature. 2017; 552(7684):187-193. PMC: 5730497. DOI: 10.1038/nature25143. View

Axelrod F, Liebes L, Gold-von Simson G, Mendoza S, Mull J, Leyne M . Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia. Pediatr Res. 2011; 70(5):480-3. PMC: 3189334. DOI: 10.1203/PDR.0b013e31822e1825. View

Vishnu N, Jadoon Khan M, Karsten F, Groschner L, Waldeck-Weiermair M, Rost R . ATP increases within the lumen of the endoplasmic reticulum upon intracellular Ca2+ release. Mol Biol Cell. 2013; 25(3):368-79. PMC: 3907277. DOI: 10.1091/mbc.E13-07-0433. View

Atwal R, Desmond C, Caron N, Maiuri T, Xia J, Sipione S . Kinase inhibitors modulate huntingtin cell localization and toxicity. Nat Chem Biol. 2011; 7(7):453-60. DOI: 10.1038/nchembio.582. View

Vidal R, Caballero B, Couve A, Hetz C . Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington's disease. Curr Mol Med. 2010; 11(1):1-12. DOI: 10.2174/156652411794474419. View

Niefind K, Putter M, Guerra B, Issinger O, Schomburg D . GTP plus water mimic ATP in the active site of protein kinase CK2. Nat Struct Biol. 1999; 6(12):1100-3. DOI: 10.1038/70033. View

Mochel F, Haller R . Energy deficit in Huntington disease: why it matters. J Clin Invest. 2011; 121(2):493-9. PMC: 3026743. DOI: 10.1172/JCI45691. View

Nath S, Munsie L, Truant R . A huntingtin-mediated fast stress response halting endosomal trafficking is defective in Huntington's disease. Hum Mol Genet. 2014; 24(2):450-62. PMC: 4275073. DOI: 10.1093/hmg/ddu460. View

10.

. Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell. 2015; 162(3):516-26. PMC: 4524551. DOI: 10.1016/j.cell.2015.07.003. View

11.

Arbez N, Ratovitski T, Roby E, Chighladze E, Stewart J, Ren M . Post-translational modifications clustering within proteolytic domains decrease mutant huntingtin toxicity. J Biol Chem. 2017; 292(47):19238-19249. PMC: 5702665. DOI: 10.1074/jbc.M117.782300. View

12.

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

13.

Tsutakawa S, Lafrance-Vanasse J, Tainer J . The cutting edges in DNA repair, licensing, and fidelity: DNA and RNA repair nucleases sculpt DNA to measure twice, cut once. DNA Repair (Amst). 2014; 19:95-107. PMC: 4051888. DOI: 10.1016/j.dnarep.2014.03.022. View

14.

Kumar A, Ratan R . Oxidative Stress and Huntington's Disease: The Good, The Bad, and The Ugly. J Huntingtons Dis. 2016; 5(3):217-237. PMC: 5310831. DOI: 10.3233/JHD-160205. View

15.

Othman E, Naseem M, Awad E, Dandekar T, Stopper H . The Plant Hormone Cytokinin Confers Protection against Oxidative Stress in Mammalian Cells. PLoS One. 2016; 11(12):e0168386. PMC: 5179003. DOI: 10.1371/journal.pone.0168386. View

16.

Hensman Moss D, Pardinas A, Langbehn D, Lo K, Leavitt B, Roos R . Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study. Lancet Neurol. 2017; 16(9):701-711. DOI: 10.1016/S1474-4422(17)30161-8. View

17.

Olsten M, Litchfield D . Order or chaos? An evaluation of the regulation of protein kinase CK2. Biochem Cell Biol. 2005; 82(6):681-93. DOI: 10.1139/o04-116. View

18.

MacDonald M . Huntingtin: alive and well and working in middle management. Sci STKE. 2003; 2003(207):pe48. DOI: 10.1126/stke.2003.207.pe48. View

19.

Rattan S, Clark B . Kinetin delays the onset of ageing characteristics in human fibroblasts. Biochem Biophys Res Commun. 1994; 201(2):665-72. DOI: 10.1006/bbrc.1994.1752. View

20.

Wanker E, Scherzinger E, Heiser V, Sittler A, EICKHOFF H, Lehrach H . Membrane filter assay for detection of amyloid-like polyglutamine-containing protein aggregates. Methods Enzymol. 1999; 309:375-86. DOI: 10.1016/s0076-6879(99)09026-6. View