ALS-Associated FUS Mutations Result in Compromised FUS Alternative Splicing and Autoregulation

PLoS Genetics

Volumn 9, Issue 10, 2013, Pages

  Zhou, Yueqin ^a,b   Liu, Songyan ^a,b   Liu, Guodong ^a,b   Öztürk, Arzu ^a,b   Hicks, Geoffrey G ^a,b  

^a UNIVERSITY OF MANITOBA   (Canada)

^b UNIVERSITY OF MANITOBA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; FUSED IN SARCOMA PROTEIN; ENHANCED GREEN FLUORESCENT PROTEIN; GREEN FLUORESCENT PROTEIN; RNA BINDING PROTEIN; RNA PRECURSOR;

ALTERNATIVE RNA SPLICING; AMYOTROPHIC LATERAL SCLEROSIS; ARTICLE; AUTOREGULATION; BINDING AFFINITY; CONTROLLED STUDY; CYTOPLASM; EXON; FUS GENE; GENE; GENE FUNCTION; GENE MUTATION; GENE TARGETING; HUMAN; HUMAN CELL; INTRON; NERVE DEGENERATION; NUCLEAR LOCALIZATION SIGNAL; NUCLEOTIDE SEQUENCE; PATHOGENESIS; PROTEIN AGGREGATION; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN RNA BINDING; RNA PROCESSING; BIOSYNTHESIS; GENE EXPRESSION REGULATION; GENETICS; HEK293 CELL LINE; HELA CELL LINE; MUTATION; PATHOLOGY;

ALTERNATIVE SPLICING; AMYOTROPHIC LATERAL SCLEROSIS; CYTOPLASM; EXONS; GENE EXPRESSION REGULATION; GREEN FLUORESCENT PROTEINS; HEK293 CELLS; HELA CELLS; HUMANS; INTRONS; MUTATION; RNA PRECURSORS; RNA-BINDING PROTEIN FUS;

EID: 84887271147     PISSN: 15537390     EISSN: 15537404     Source Type: Journal    
DOI: 10.1371/journal.pgen.1003895     Document Type: Article

References (73)

1. Andersen PM, Al-Chalabi A, (2011) Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nature Reviews Neurology 7: 603-615.
2. Da Cruz S, Cleveland DW, (2011) Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Current Opinion in Neurobiology 21: 904-919.
3. Robberecht W, Philips T, (2013) The changing scene of amyotrophic lateral sclerosis. Nature Reviews Neuroscience 14: 248-264.
4. Lagier-Tourenne C, Cleveland DW, (2009) Rethinking ALS: The FUS about TDP-43. Cell 136: 1001-1004.
5. Lagier-Tourenne C, Polymenidou M, Cleveland DW, (2010) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Human Molecular Genetics 19: R46-R64.
6. Kino Y, Washizu C, Aquilanti E, Okuno M, Kurosawa M, et al. (2010) Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. Nucleic Acids Research 39: 2781-2798.
7. Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, et al. (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. The EMBO Journal 29: 2841-2857.
8. Kwiatkowski TJ, Bosco DA, LeClerc AL, Tamrazian E, Vanderburg CR, et al. (2009) Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis. Science 323: 1205-1208.
9. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, et al. (2009) Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6. Science 323: 1208-1211.
10. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, et al. (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132: 2922-2931.
11. Bosco DA, Lemay N, Ko HK, Zhou H, Burke C, et al. (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Human Molecular Genetics 19: 4160-4175.
12. Mackenzie IRA, Ansorge O, Strong M, Bilbao J, Zinman L, et al. (2011) Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neuropathologica 122: 87-98.
13. Waibel S, Neumann M, Rosenbohm A, Birve A, Volk AE, et al. (2013) Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany. Eur J Neurol 20: 540-546.
14. Fushimi K, Long C, Jayaram N, Chen X, Li L, et al. (2011) Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy. Protein & Cell 2: 141-149.
15. Chen Y, Yang M, Deng J, Chen X, Ye Y, et al. (2011) Expression of human FUS protein in Drosophila leads to progressive neurodegeneration. Protein Cell 2: 477-486.
16. Huang C, Zhou H, Tong J, Chen H, Liu YJ, et al. (2011) FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet 7: e1002011.
17. Murakami T, Yang SP, Xie L, Kawano T, Fu D, et al. (2011) ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism. Human Molecular Genetics 21: 1-9.
18. Kabashi E, Bercier V, Lissouba A, Liao M, Brustein E, et al. (2011) FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis. PLoS Genet 7: e1002214.
19. Iijima KM, Sasayama H, Shimamura M, Tokuda T, Azuma Y, et al. (2012) Knockdown of the Drosophila Fused in Sarcoma (FUS) Homologue Causes Deficient Locomotive Behavior and Shortening of Motoneuron Terminal Branches. PLoS One 7: e39483.
20. Andersson MK, Ståhlberg A, Arvidsson Y, Olofsson A, Semb H, et al. (2008) The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response. BMC Cell Biology 9: 37.
21. Zinszner H, Sok J, Immanuel D, Yin Y, Ron D, (1997) TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. J Cell Sci 110 (Pt 15): 1741-1750.
22. Baechtold H, Kuroda M, Sok J, Ron D, Lopez BS, et al. (1999) Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation. J Biol Chem 274: 34337-34342.
23. Law WJ, Cann KL, Hicks GG, (2006) TLS, EWS and TAF15: a model for transcriptional integration of gene expression. Brief Funct Genomic Proteomic 5: 8-14.
24. Tan AY, Manley JL, (2009) The TET Family of Proteins: Functions and Roles in Disease. Journal of Molecular Cell Biology 1: 82-92.
25. Dormann D, Haass C, (2013) Fused in sarcoma (FUS): An oncogene goes awry in neurodegeneration. Mol Cell Neurosci E-pub ahead of print. doi: 10.1016/j.mcn.2013.03.006.
26. Anthony K, Gallo JM, (2010) Aberrant RNA processing events in neurological disorders. Brain Res 1338: 67-77.
27. Rabin SJ, Kim JM, Baughn M, Libby RT, Kim YJ, et al. (2010) Sporadic ALS has compartment-specific aberrant exon splicing and altered cell-matrix adhesion biology. Hum Mol Genet 19: 313-328.
28. Ishigaki S, Masuda A, Fujioka Y, Iguchi Y, Katsuno M, et al. (2012) Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. Sci Rep 2: 529.
29. Rogelj B, Easton LE, Bogu GK, Stanton LW, Rot G, et al. (2012) Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci Rep 2: 603.
30. Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M, et al. (2012) Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci 15: 1488-1497.
31. Hoell JI, Larsson E, Runge S, Nusbaum JD, Duggimpudi S, et al. (2011) RNA targets of wild-type and mutant FET family proteins. Nature Structural & Molecular Biology 18: 1428-1431.
32. Nakaya T, Alexiou P, Maragkakis M, Chang A, Mourelatos Z, (2013) FUS regulates genes coding for RNA-binding proteins in neurons by binding to their highly conserved introns. Rna 19: 498-509.
33. Ji H, Jiang H, Ma W, Johnson DS, Myers RM, et al. (2008) An integrated software system for analyzing ChIP-chip and ChIP-seq data. Nature Biotechnology 26: 1293-1300.
34. Colombrita C, Onesto E, Megiorni F, Pizzuti A, Baralle FE, et al. (2012) TDP-43 and FUS RNA-binding Proteins Bind Distinct Sets of Cytoplasmic Messenger RNAs and Differently Regulate Their Post-transcriptional Fate in Motoneuron-like Cells. Journal of Biological Chemistry 287: 15635-15647.
35. Xue Y, Zhou Y, Wu T, Zhu T, Ji X, et al. (2009) Genome-wide Analysis of PTB-RNA Interactions Reveals a Strategy Used by the General Splicing Repressor to Modulate Exon Inclusion or Skipping. Molecular Cell 36: 996-1006.
36. Licatalosi DD, Mele A, Fak JJ, Ule J, Kayikci M, et al. (2008) HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456: 464-469.
37. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, et al. (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38: 576-589.
38. Zhang MQ, (1998) Statistical features of human exons and their flanking regions. Hum Mol Genet 7: 919-932.
39. Huang da W, Sherman BT, Lempicki RA, (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44-57.
40. Lerga A, Hallier M, Delva L, Orvain C, Gallais I, et al. (2001) Identification of an RNA binding specificity for the potential splicing factor TLS. J Biol Chem 276: 6807-6816.
41. Boutz PL, Stoilov P, Li Q, Lin CH, Chawla G, et al. (2007) A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes & Development 21: 1636-1652.
42. Xie J, Black DL, (2001) A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels. Nature 410: 936-939.
43. Rossbach O, Hung LH, Schreiner S, Grishina I, Heiner M, et al. (2009) Auto- and Cross-Regulation of the hnRNP L Proteins by Alternative Splicing. Molecular and Cellular Biology 29: 1442-1451.
44. Mitchell JC, McGoldrick P, Vance C, Hortobagyi T, Sreedharan J, et al. (2013) Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol 125: 273-288.
45. Sun Z, Diaz Z, Fang X, Hart MP, Chesi A, et al. (2011) Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol 9: e1000614.
46. Vance C, Scotter EL, Nishimura AL, Troakes C, Mitchell JC, et al. (2013) ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules. Human Molecular Genetics 22: 2676-2688.
47. Spitali P, Aartsma-Rus A, (2012) Splice Modulating Therapies for Human Disease. Cell 148: 1085-1088.
48. Wilton SD, Fall AM, Harding PL, McClorey G, Coleman C, et al. (2007) Antisense Oligonucleotide-induced Exon Skipping Across the Human Dystrophin Gene Transcript. Molecular Therapy 15: 1288-1296.
49. Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, et al. (2010) Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes & Development 24: 1634-1644.
50. Wollerton MC, Gooding C, Wagner EJ, Garcia-Blanco MA, Smith CW, (2004) Autoregulation of polypyrimidine tract binding protein by alternative splicing leading to nonsense-mediated decay. Mol Cell 13: 91-100.
51. Dredge BK, Stefani G, Engelhard CC, Darnell RB, (2005) Nova autoregulation reveals dual functions in neuronal splicing. Embo J 24: 1608-1620.
52. Ayala YM, De Conti L, Avendaño-Vázquez SE, Dhir A, Romano M, et al. (2010) TDP-43 regulates its mRNA levels through a negative feedback loop. The EMBO Journal 30: 277-288.
53. Hicks GG, Singh N, Nashabi A, Mai S, Bozek G, et al. (2000) Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat Genet 24: 175-179.
54. Spitzer JI, Ugras S, Runge S, Decarolis P, Antonescu C, et al. (2011) mRNA and protein levels of FUS, EWSR1, and TAF15 are upregulated in liposarcoma. Genes Chromosomes Cancer 50: 338-347.
55. Mills KI, Walsh V, Gilkes AF, Sweeney MC, Mirza T, et al. (2000) High FUS/TLS expression in acute myeloid leukaemia samples. Br J Haematol 108: 316-321.
56. Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, et al. (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nature Neuroscience 14: 459-468.
57. Ling S-C, Polymenidou M, Cleveland Don W, (2013) Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis. Neuron 79: 416-438.
58. Suzuki N, Kato S, Kato M, Warita H, Mizuno H, et al. (2012) FUS/TLS-immunoreactive neuronal and glial cell inclusions increase with disease duration in familial amyotrophic lateral sclerosis with an R521C FUS/TLS mutation. J Neuropathol Exp Neurol 71: 779-788.
59. Kameoka S, Duque P, Konarska MM, (2004) p54(nrb) associates with the 5′ splice site within large transcription/splicing complexes. Embo J 23: 1782-1791.
60. Leichter M, Marko M, Ganou V, Patrinou-Georgoula M, Tora L, et al. (2011) A fraction of the transcription factor TAF15 participates in interactions with a subset of the spliceosomal U1 snRNP complex. Biochim Biophys Acta 1814: 1812-1824.
61. Yeo GW, Coufal NG, Liang TY, Peng GE, Fu XD, et al. (2009) An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells. Nat Struct Mol Biol 16: 130-137.
62. Ray P, Kar A, Fushimi K, Havlioglu N, Chen X, et al. (2011) PSF suppresses tau exon 10 inclusion by interacting with a stem-loop structure downstream of exon 10. J Mol Neurosci 45: 453-466.
63. Han K, Yeo G, An P, Burge CB, Grabowski PJ, (2005) A combinatorial code for splicing silencing: UAGG and GGGG motifs. PLoS Biol 3: e158.
64. Dichmann DS, Harland RM, (2012) fus/TLS orchestrates splicing of developmental regulators during gastrulation. Genes & Development 26: 1351-1363.
65. Ule J, Jensen K, Mele A, Darnell RB, (2005) CLIP: A method for identifying protein-RNA interaction sites in living cells. Methods 37: 376-386.
66. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ, (1990) Basic local alignment search tool. J Mol Biol 215: 403-410.
67. Blankenberg D, Coraor N, Von Kuster G, Taylor J, Nekrutenko A, (2011) Integrating diverse databases into an unified analysis framework: a Galaxy approach. Database (Oxford) 2011: bar011.
68. Langmead B, Trapnell C, Pop M, Salzberg SL, (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10: R25.
69. Fujita PA, Rhead B, Zweig AS, Hinrichs AS, Karolchik D, et al. (2011) The UCSC Genome Browser database: update 2011. Nucleic Acids Res 39: D876-882.
70. Sanford JR, Wang X, Mort M, VanDuyn N, Cooper DN, et al. (2008) Splicing factor SFRS1 recognizes a functionally diverse landscape of RNA transcripts. Genome Research 19: 381-394.
71. Nagaraj N, Wisniewski JR, Geiger T, Cox J, Kircher M, et al. (2011) Deep proteome and transcriptome mapping of a human cancer cell line. Mol Syst Biol 7: 548.
72. Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, et al. (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14: 128.
73. Cooper C, Guo J, Yan Y, Chooniedass-Kothari S, Hube F, et al. (2009) Increasing the relative expression of endogenous non-coding Steroid Receptor RNA Activator (SRA) in human breast cancer cells using modified oligonucleotides. Nucleic Acids Research 37: 4518-4531.