Antisense oligonucleotide-mediated exon skipping as a strategy to reduce proteolytic cleavage of ataxin-3

Scientific Reports

Volumn 6, Issue , 2016, Pages

  Toonen, Lodewijk J A ^a   Schmidt, Iris ^a   Luijsterburg, Martijn S ^a   Van Attikum, Haico ^a   Van Roon Mom, Willeke M C ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; ATAXIN 3; ATXN3 PROTEIN, HUMAN; CALPAIN; CAPN2 PROTEIN, HUMAN; MUTANT PROTEIN; POLYUBIQUITIN; REPRESSOR PROTEIN; RNA PRECURSOR;

BINDING SITE; CELL LINE; CHEMISTRY; DOUBLE STRANDED DNA BREAK; EXON; GENETICS; HUMAN; MACHADO JOSEPH DISEASE; METABOLISM; PROTEIN DEGRADATION;

ATAXIN-3; BINDING SITES; CALPAIN; CELL LINE; DNA BREAKS, DOUBLE-STRANDED; EXONS; HUMANS; MACHADO-JOSEPH DISEASE; MUTANT PROTEINS; OLIGONUCLEOTIDES, ANTISENSE; POLYUBIQUITIN; PROTEOLYSIS; REPRESSOR PROTEINS; RNA PRECURSORS;

EID: 84991058710     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep35200     Document Type: Article

References (47)

1. Riess, O., Rub, U., Pastore, A., Bauer, P., Schols, L. SCA3: neurological features, pathogenesis and animal models. Cerebellum 7, 125-137, doi: 10.1007/s12311-008-0013-4 (2008).
2. Cummings, C. J., Zoghbi, H. Y. Trinucleotide repeats: mechanisms and pathophysiology. Annual review of genomics and human genetics 1, 281-328, doi: 10.1146/annurev.genom.1.1.281 (2000).
3. Bradford, J. W., Li, S., Li, X. J. Polyglutamine toxicity in non-neuronal cells. Cell research 20, 400-407, doi: 10.1038/cr.2010.32 (2010).
4. Winborn, B. J. et al. The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem 283, 26436-26443, doi: 10.1074/jbc.M803692200 (2008).
5. Bettencourt, C. et al. Increased transcript diversity: novel splicing variants of Machado-Joseph disease gene (ATXN3). Neurogenetics 11, 193-202, doi: 10.1007/s10048-009-0216-y (2010).
6. Matos, C. A., de Macedo-Ribeiro, S., Carvalho, A. L. Polyglutamine diseases: the special case of ataxin-3 and Machado-Joseph disease. Prog Neurobiol 95, 26-48, doi: 10.1016/j.pneurobio.2011.06.007 (2011).
7. Evers, M. M., Toonen, L. J., van Roon-Mom, W. M. Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies. Mol Neurobiol 49, 1513-1531, doi: 10.1007/s12035-013-8596-2 (2014).
8. Berke, S. J., Schmied, F. A., Brunt, E. R., Ellerby, L. M., Paulson, H. L. Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3. J Neurochem 89, 908-918, doi: 10.1111/j.1471-4159.2004.02369.x (2004).
9. Wellington, C. L. et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 273, 9158-9167 (1998).
10. Hubener, J. et al. Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). Hum Mol Genet 22, 508-518, doi: 10.1093/hmg/dds449 (2013).
11. Goti, D. et al. A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci 24, 10266-10279, doi: 10.1523/JNEUROSCI.2734-04.2004 (2004).
12. Haacke, A., Hartl, F. U., Breuer, P. Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3. J Biol Chem 282, 18851-18856, doi: 10.1074/jbc.M611914200 (2007).
13. Simoes, A. T. et al. Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease. Brain 135, 2428-2439, doi: 10.1093/brain/aws177 (2012).
14. Aartsma-Rus, A. et al. Functional analysis of 114 exon-internal AONs for targeted DMD exon skipping: indication for steric hindrance of SR protein binding sites. Oligonucleotides 15, 284-297, doi: 10.1089/oli.2005.15.284 (2005).
15. Spitali, P., Aartsma-Rus, A. Splice modulating therapies for human disease. Cell 148, 1085-1088, doi: 10.1016/j.cell.2012.02.014 (2012).
16. Evers, M. M., Toonen, L. J., van Roon-Mom, W. M. Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv Drug Deliv Rev 87, 90-103, doi: 10.1016/j.addr.2015.03.008 (2015).
17. Chiriboga, C. A. et al. Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology 86, 890-897, doi: 10.1212/wnl.0000000000002445 (2016).
18. Miller, T. M. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 12, 435-442, doi: 10.1016/S1474-4422(13)70061-9 (2013).
19. Maquat, L. E. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nature reviews. Molecular cell biology 5, 89-99, doi: 10.1038/nrm1310 (2004).
20. Luijsterburg, M. S. et al. A new noncatalytic role for ubiquitin ligase RNF8 in unfolding higherorder chromatin structure. The EMBO Journal 31, 2511-2527, doi: 10.1038/emboj.2012.104 (2012).
21. Janicki, S. M. et al. From Silencing to Gene Expression: Real-Time Analysis in Single Cells. Cell 116, 683-698, doi: http://dx.doi. org/10.1016/S0092-8674(04)00171-0 (2004).
22. Gao, R. et al. Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3. PLoS genetics 11, e1004834, doi: 10.1371/journal.pgen.1004834 (2015).
23. Weinfeld, M., Mani, R. S., Abdou, I., Aceytuno, R. D., Glover, J. N. Tidying up loose ends: the role of polynucleotide kinase/phosphatase in DNA strand break repair. Trends in biochemical sciences 36, 262-271, doi: 10.1016/j.tibs.2011.01.006 (2011).
24. Koch, P. et al. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480, 543-546, doi: 10.1038/nature10671 (2011).
25. Haacke, A. et al. Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of nonexpanded ataxin-3. Hum Mol Genet 15, 555-568, doi: 10.1093/hmg/ddi472 (2006).
26. Song, J. et al. Cascleave: towards more accurate prediction of caspase substrate cleavage sites. Bioinformatics (Oxford, England) 26, 752-760, doi: 10.1093/bioinformatics/btq043 (2010).
27. Boeddrich, A. et al. An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis. The EMBO Journal 25, 1547-1558, doi: 10.1038/sj.emboj.7601043 (2006).
28. Zhong, X., Pittman, R. N. Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates. Hum Mol Genet 15, 2409-2420, doi: 10.1093/hmg/ddl164 (2006).
29. Burnett, B., Li, F., Pittman, R. N. The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet 12, 3195-3205, doi: 10.1093/hmg/ddg344 (2003).
30. Mao, Y. et al. Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proceedings of the National Academy of Sciences of the United States of America 102, 12700-12705, doi: 10.1073/pnas.0506344102 (2005).
31. Laco, M. N., Cortes, L., Travis, S. M., Paulson, H. L., Rego, A. C. Valosin-containing protein (VCP/p97) is an activator of wild-type ataxin-3. Plos One 7, e43563, doi: 10.1371/journal.pone.0043563 (2012).
32. Chatterjee, A. et al. The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3-phosphatase in spinocerebellar ataxia type 3 pathogenesis. Plos genetics 11, e1004749, doi: 10.1371/journal.pgen.1004749 (2015).
33. Caldecott, K. W. Single-strand break repair and genetic disease. Nature reviews. Genetics 9, 619-631, doi: 10.1038/nrg2380 (2008).
34. McKinnon, P. J. DNA repair deficiency and neurological disease. Nat Rev Neurosci 10, 100-112 (2009).
35. Schneider, L. et al. Differentiation of SH-SY5Y cells to a neuronal phenotype changes cellular bioenergetics and the response to oxidative stress. Free radical biology & medicine 51, 2007-2017, doi: 10.1016/j.freeradbiomed.2011.08.030 (2011).
36. Forster, J. I. et al. Characterization of Differentiated SH-SY5Y as Neuronal Screening Model Reveals Increased Oxidative Vulnerability. Journal of biomolecular screening 21, 496-509, doi: 10.1177/1087057115625190 (2016).
37. Rigo, F. et al. Pharmacology of a central nervous system delivered 2-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. The Journal of pharmacology and experimental therapeutics 350, 46-55, doi: 10.1124/jpet.113.212407 (2014).
38. Aartsma-Rus, A. Overview on AON design. Methods Mol Biol 867, 117-129, doi: 10.1007/978-1-61779-767-5-8 (2012).
39. Desmet, F. O. et al. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37, e67, doi: 10.1093/nar/gkp215 (2009).
40. Zuker, M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31, 3406-3415 (2003).
41. Aartsma-Rus, A. et al. Guidelines for antisense oligonucleotide design and insight into splice-modulating mechanisms. Molecular therapy : the journal of the American Society of Gene Therapy 17, 548-553, doi: 10.1038/mt.2008.205 (2009).
42. Evers, M. M. et al. Preventing formation of toxic N-terminal huntingtin fragments through antisense oligonucleotide-mediated protein modification. Nucleic Acid Ther 24, 4-12, doi: 10.1089/nat.2013.0452 (2014).
43. Rozen, S., Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132, 365-386 (2000).
44. Ruijter, J. M. et al. Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res 37, e45, doi: 10.1093/nar/gkp045 (2009).
45. Schmidt, T. et al. An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol 8, 669-679 (1998).
46. Evers, M. M. et al. Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: removal of the CAG containing exon. Neurobiol Dis 58, 49-56, doi: 10.1016/j.nbd.2013.04.019 (2013).
47. Typas, D. et al. The de-ubiquitylating enzymes USP26 and USP37 regulate homologous recombination by counteracting RAP80. Nucleic Acids Res 44, 2976, doi: 10.1093/nar/gkv1480 (2016).