Genetic Suppression of Polyglutamine Toxicity in Drosophila Parsa Kazemi-Esfarjani, * Seymour Benzer

A Drosophila model for Huntington's and other polyglutamine diseases was used to screen for genetic factors modifying the degeneration caused by expression of polyglutamine in the eye. Among 7000 P-element insertions, several suppressor strains were isolated, two of which led to the discovery of the suppressor genes described here. The predicted product of one, dHDJ1, is homologous to human heat shock protein 40/HDJ1. That of the second, dTPR2, is homologous to the human tetratricopeptide repeat protein 2. Each of these molecules contains a chaperone-related J domain. Their suppression of polyglutamine toxicity was verified in transgenic flies.

Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. *   To whom correspondence should be addressed. E-mail: parsa@its.caltech.edu

Expanded polyCAG tracts in the genes for Huntington's disease (HD) and at least seven other disorders are associated with hereditary neurodegeneration (1). The polyCAGs are translated to polyglutamines, which form cytoplasmic and/or nuclear aggregates and produce toxic effects (1, 2). One approach to the identification of proteins that can modify polyglutamine aggregation and toxicity is the isolation of enhancer and suppressor genes. For this purpose, the Drosophila eye offers a sensitive model system (3, 4). In a candidate gene approach, a baculovirus antiapoptotic gene, p35, and a human heat shock protein (HSP70, encoded by the HSPA1L gene) suppressed polyglutamine-dependent degeneration in the eye (3, 5). Here an alternative approach is described: screening the fly genome for genes that dominantly modify the toxicity of polyglutamine.

Using a polymerase chain reaction (PCR) method, we synthesized polyCAGs of short (20 CAGs) and expanded (127 CAGs) lengths (6). These were placed in transgenic constructs cis to the yeast upstream activating sequence (UAS). Their expression was activated in genetic crosses trans to the yeast GAL4 transcription factor, expression of which was in turn regulated by the eye-specific promoter GMR upstream of the yeast GAL4 cDNA (7-9). GMR is composed of five tandem copies of a response element derived from the rhodopsin 1 gene promoter, a binding site for the eye-specific transcription factor GLASS (10). This promoter enhances the expression of the reporter gene in all retinal cell types as they develop. Flies carrying GMR-GAL4 were crossed with three independently generated UAS-polyCAG transgenic lines carrying the short 20-CAG repeat (UAS-20Q) and with those containing the expanded 127-CAG repeat (UAS-127Q), and in all cases were tagged with a hemagglutinin (HA) epitope sequence (11).

In all three GMR-GAL4/UAS-20Q lines, flies eclosed as adults with eyes that were morphologically normal and had normal pigment distribution. In contrast, the three lines of GMR-GAL4/UAS-127Q had severely abnormal eyes (Fig. 1). Immunolabeling of the HA tag in cryostat sections of GMR-GAL4/UAS-127Q flies showed aggregates in the remnants of the retina (12). No staining was observed in GMR-GAL4/UAS-20Q flies, possibly because of a

lack of aggregation or rapid turnover of the shorter protein. Heterozygous GMR-GAL4 flies expressing GAL4 alone and all three UAS-127Q lines without GMR-GAL4 had normal external and internal eye morphology and pigment distribution.

Fig. 1. Genetic suppression of the toxic effect of 127Q in the fly eye. SEM, scanning electron microscopy; FITC, frozen sections labeled with antibody to the HA tag on 127Q peptide (green); FITC+DAPI, double exposure with DAPI to stain nuclei (blue). (A) Control, expressing GAL4 regulated by GMR, the eye-specific enhancer/promoter, in the absence of 127Q. The red pigmentation is due to expression of the white+ gene marker on the GMR P element. No aggregates are observed with FITC. DAPI shows a relatively normal arrangement of nuclei. (B) Flies expressing 127Q peptide driven by GMR-GAL4. The eye has roughly normal size but is severely malformed. Light microscopy shows the absence of pigmentation. FITC shows numerous fluorescent polyglutamine aggregates, mostly localized to nuclei, as seen by overlap with DAPI. (C) Suppressor P-element insertion EU3500 restores the external eye structure and pigmentation. FITC and DAPI stains show improved internal retinal structure, despite the presence of polyglutamine aggregates. (D) Confirmation of suppression in transgenic flies with dhdJ1 cDNA, corresponding to the gene 3' of the EU3500 P-element insertion. Again, the eye structure is largely restored despite the fact that polyglutamine aggregates are still present. As indicated by overlap of DAPI and FITC staining, the polyglutamine nuclear inclusions are present in the peripheral retina, whereas in the proximal retina the FITC staining alone indicates that there are cytoplasmic inclusions as well. (E) A second suppressor P-element insertion, EU3220, also improves the external eye structure and pigmentation, albeit less effectively than EU3500. FITC and DAPI stains show improvement of internal retinal structure with some retinal degeneration. (F) Confirmation of suppression in transgenic flies with dtrp2 cDNA, corresponding to the gene 3' of the EU3220 P-element insertion. [View Larger Version of this Image (108K GIF file)]

GMR-GAL4/UAS-127Q flies have severe externally visible eye abnormalities (Fig. 1) and were used to screen for dominant modifiers of the toxicity of the 127Q repeat by examining the genes in the vicinity of a series of P-element chromosomal insertion sites. This was done by crossing them with some 7000 de novo-generated autosomal P-element insertion strains (13) and assessing the F1 progeny for suppression or enhancement of the eye phenotype. Thirty lines were established that suppressed the polyglutamine-dependent eye degeneration in heterozygous flies and 29 lines were made that enhanced it (14). Plasmid rescue of the P elements and their flanking genomic DNA was performed (15), and cDNA corresponding to

the P-element insertion site was used to test its ability to suppress the polyglutamine toxicity. Here we report the results for the first two lines for which the suppression effects have been directly confirmed.

In the first line, EU3500, the genomic sequence, starting 98 base pairs (bp) downstream of the P element, matched an expressed sequence tag (EST) in the Berkeley Drosophila Genome Project (BDGP) database (15). At least three independent cDNA clones in the database had similar sequences but different lengths of 3' UTR. For testing, GH26396 (16) was chosen, which is a 1711-bp cDNA that encodes dHDJ1, a predicted protein of 334 amino acids and a molecular weight of 37 kD, which has an NH2-terminal J domain and homology to human HSP40/HDJ1 (54% identity and 72% similarity) (Fig. 2) (17-19).

Fig. 2. Alignment of Drosophila (dHDJ1)and human HSP40 (hHsp40/HDJ1). The amino acid sequences are 54% identical and 72% similar (37). The J regions (23) are underlined. These are 74% identical and 88% similar. Light gray shading indicates similarity; dark gray shading indicates identity. [View Larger Version of this Image (48K GIF file)]

For the second suppressor line, EU3220, the sequence starting 293 bp downstream of the P element matched an EST, and the corresponding cDNA clone GH09432 (16) was sequenced. The P-element insertion was 649 bp 5' of the open reading frame (ORF) of a 2239-bp cDNA, corresponding to a predicted protein of 508 amino acids and a molecular weight of 58 kD that contains 7 tetratricopeptide repeats and a COOH-terminal J domain. A protein database search revealed high homology (46% identity and 67% similarity) between this and the human tetratricopeptide repeat protein 2 (TPR2) (20, 21) (Fig. 3). We have therefore named it Drosophila tetratricopeptide repeat protein 2 (dTPR2).

Fig. 3. Alignment of Drosophila (dTPR2) and the human tetratricopeptide repeat protein 2 (hTPR2) (21). The amino acid sequences are 46% identical and 67% similar (37). The J regions (underlined) are 74% identical and 93% similar. In addition, there are seven

tetratricopeptide repeat motifs, indicated by arrows. Shading is the same as in Fig. 2. [View Larger Version of this Image (77K GIF file)]

As seen by scanning electron microscopy, the abnormal eyes of GMR-GAL4/UAS-127Q flies were dramatically improved in the presence of the suppressor P-element insertion in strain EU3500 (Fig. 1C). With this insertion, the eye preserves its globular structure, pigmentation, and a uniform bristle arrangement. Although the result is weaker than in EU3500, the suppressor P-element in strain EU3220 also showed a dramatic effect (Fig. 1E).

The internal structure of the eye was examined in horizontal cryostat head sections. In unsuppressed GMR-GAL4/UAS-127Q flies, the structure was badly deformed and immunolabeling of the HA-tagged polyglutamine peptides showed numerous aggregates of fluorescein isothiocyanate (FITC) (Fig. 1B). In the presence of the suppressor insertion in strain EU3500, the retinal structure was vastly improved (Fig. 1C) even though the number of aggregates remained similar. In the presence of EU3220, the effect was similar but weaker (Fig. 1E).

To examine whether the gene immediately 3' to the EU3500 insertion was indeed responsible for the observed suppression, the corresponding cDNA in GH26396, which contains the coding sequences for dHDJ1, was placed in the transgenic vector (22) and microinjected into early-stage fly embryos. All three independent transgenic lines, each carrying a heterozygous autosomal insertion of UAS-dhdJ1 in the presence of GMR-GAL4/UAS-127Q, closely reproduced the phenotype of the EU3500 line (Fig. 1D). This confirmed that the suppression of polyglutamine-dependent degeneration of the eye by the P-element insertion and its transgenic counterparts was indeed due to the action of dHDJ1. Similarly, the transgenesis test, which uses three independent transgenic lines carrying a heterozygous insertion of UAS-dtpr2 together with GMR-GAL4/UAS-127Q, confirmed that suppression by the EU3220 P element and its transgenic counterpart wasdue to the action of dTPR2 (Fig. 1F).

Drosophila dHDJ1 and dTPR2 each have a J domain, a stretch of about 70 amino acids found in J proteins that stimulates the adenosine triphosphatase activity of HSP70 (23), which causes the closure of its peptide-binding pocket, thus trapping protein substrates (24). J proteins also independently bind other proteins having secondary and tertiary structure (25).

Direct evidence for the role of HSPs, particularly J proteins, in preventing protein aggregation has been provided in vitro by showing that a fivefold molar excess of Escherichia coli DnaJ completely suppresses aggregation of a substrate protein (bovine mitochondrial rhodanese) (26). J proteins may also play a role in the proteasome degradation pathway because the J domain of the simian virus 40 (SV40) large T antigen (TAg) was required for proteasome-dependent degradation of p130 (related to retinoblastoma tumor suppressor protein, pRB) in human osteosarcoma cell line U-2 OS (27). In fact, the J domains of two other paralogs of human HSP40, HDJ2 (also known as DNAJ2), or HSJ1 could substitute for the J domain in SV40 TAg, and substitution of a glutamine for a conserved histidine in the J domains could abolish that effect.

Drosophila TPR2 may also act as a suppressor in another way. TPR domains are made of 3 to 16 degenerate repeats of a 34-amino acid stretch, each of which forms a pair of antiparallel  helices (28). Multiple tandem TPR units assemble into right-handed superhelical structures

that are suited for protein-protein interfaces. They are found in proteins involved in various functions, including protein import, neurogenesis, stress response, and chaperone action (21, 29). The human TPR2 was isolated from a HeLa cell cDNA library in a two-hybrid screen, using as "bait" a 271-amino acid fragment of guanine triphosphatase (GTPase)-activating protein-related domain (GRD) of neurofibromin, the neurofibromatosis type 1 (NF1) gene product (21). Neurofibromin stimulates the GTPase activity of p21 Ras and converts it from the active form (Ras-GTP) to its inactive form (Ras-GDP) (30). Conceivably, overexpression of dTPR2 in the fly eye inhibits the Drosophila homolog of neurofibromin (dNF1) (31) by masking its GRD. This would increase the activity of Ras-GTP, which is known to inhibit the proapoptotic head involution defective (HID) protein (32) and enhance the survival of eye cells.

In cultured cells transfected with full-length ataxin-1 or the androgen receptor, each with an expanded polyglutamine, coexpression of HDJ2/HSDJ resulted in 40 to 50% reduction in the number of cells containing aggregates (33, 34). Similar to the effect of HSPA1L, the EU3500 or EU3220 P elements or expression of their transgenic counterparts inhibited deterioration of the eye structure, yet the formation of aggregates was not suppressed. Because the GMR promoter acts early in eye development, it is possible that dHDJ1 and dTPR2 act at that early stage of differentiation by binding to 127Q and maintaining a nontoxic milieu, thus permitting eye development to proceed more normally. Conversely, these suppressor proteins, rather than directly interacting with 127Q peptide, may reduce its toxicity by a downstream effect.

The many additional suppressor strains already in hand may lead to discovery of other genes relevant to the pathogenesis of various polyglutamine disorders and their prophylactic or therapeutic treatment.

REFERENCES AND NOTES

1. T. W. Kim and R. E. Tanzi, Neuron 21, 657 (1998) [CrossRef] [ISI] [Medline] . 2. Y. Trottier, et al., Nature 378, 403 (1995) [CrossRef] [Medline] . 3. J. M. Warrick, et al., Cell 93, 939 (1998) [CrossRef] [ISI] [Medline] . 4. G. R. Jackson, et al., Neuron 21, 633 (1998) [CrossRef] [ISI] [Medline] ; J. L. Marsh,

et al., Hum. Mol. Genet. 9, 13 (2000) [Abstract/ Free   Full   Text] . 5. J. M. Warrick, et al., Nature Genet. 23, 425 (1999) [CrossRef] [ISI] [Medline] . 6. Because it has one of the longest known CAG tracts in the fly (20 repeats), the

prospero gene in the p139cAC1 plasmid (35) was used as a template for PCR synthesis of expanded polyCAG tracts. Primers used to amplify two fragments containing polyCAG tracts were as follows: (i) ProsBamHI3229F (5'-ATG CGC GGA TCC CAG CAG CTG GAG CAG AAC GAG GCC-3') with 5' phosphorylated-ProsAflIIR (5'-ATT GCT GTT GCC GCC GTT CTT AAG CTG TTG TTG TTG CTG TTG TTG-3') and (ii) ProsBstBIF (5'-ACC GGA GGC CCA CCG TCA TTC GAA CAG CAG CAG CAA CAG-3') with Pros3650R (5'-GCT GCG TGC GGA TTG AAG AAC GGC-3'). These fragments were digested with Bam HI (5' fragment) or Bst XI (3' fragment) and ligated with T4 DNA ligase (Gibco/BRL) into the Bam HI-Bst XI fragment of p139cAC1. After cloning and amplifying this construct in XL1 Blue strain of E. coli (Stratagene), the sequence between the two polyCAG tracts was removed by digesting with Bst BI and Afl II (or Bfr I) and trimming the overhanging ends with mung bean nuclease (New England Biolabs), followed by ligation and transformation into XL1 Blue. To synthesize polyCAG of 127 repeats, this procedure was repeated twice more. To produce UAS-20Q and UAS-127Q, polyCAG20 and

polyCAG127 and their flanking sequences were PCR-amplified by primers 5' Gln2F (5'-CGG AAT TCG CCG CCA CCA TGG GAG GCC CAC CGT CAA CCC CCC AGC AG-3') and 3' GlnR (5'-ATT GCT GTT GCC GCC GTT ACT AGT CTG TTG CTG CTG CTG TTG-3'). The PCR fragment was digested with Eco RI and Spe I and, with a Pst I-Eco RI adapter, was inserted in-frame with an HA tag DNA sequence into the Pst I-Spe I fragment of the pINDY6 transgenic vector (36). These plasmids express polyglutamine tracts flanked by 8 amino acids on the NH2-terminal side and 13 amino acids on the COOH-terminal side (MGGPPSTPQnTSRTYPYDVPDYA) (37).

7. A. H. Brand and N. Perrimon, Development 118, 401 (1993) [Abstract] . 8. M. C. Ellis, E. M. O'Neill, G. M. Rubin, Development 119, 855 (1993) [Abstract] . 9. M. Freeman, Cell 87, 651 (1996) [CrossRef] [ISI] [Medline] . 10. K. Moses and G. M. Rubin, Genes Dev. 5, 583 (1991) [Abstract/ Free   Full   Text] . 11. Flies were maintained on a mixture of corn meal, yeast, and agar at 25°C in 70%

humidity. Microinjection solutions containing the transgenic constructs were composed of the following: 13.5 µg of transgenic vector, 4.5 µg of p 25.1 transposase vector (38), 0.1 M sodium phosphate buffer (pH 7.8), and 5 mM potassium chloride, in 50 µl of aqueous solution. With Transjector 5246 and Femtotips II (Eppendorf), the transgenic constructs were microinjected into 5- to 30-min-old w1118 embryos reared at 18°C. Several transgenic lines were established for each construct. Plasmid rescue (39) and sequencing of two clones of a 127Q line, and one clone for each of the four 20Q lines, confirmed the expected polyCAG and flanking sequences in the transgenic lines.

12. Whole flies were submerged in Mirsky's fixative (National Diagnostics, Atlanta, GA) for 1 to 2 min. They were then decapitated, and the heads were placed in OCT 4583 embedding medium (Tissue-Tek, Torrance, CA), frozen on dry ice, and sectioned. Slides were dried on a 50°C hot plate for 30 s, then fixed in Mirsky's fixative for 30 min at room temperature and washed three times within 10 min with phosphate-buffered saline (PBS) and Tween 20 (PBS/Tween 20, 0.1%). The sections were blocked with 1% PBS and bovine serum albumin fraction V (Sigma), then covered with primary polyclonal antibody to HA (1 µg/ml) (Y-11; Santa Cruz Biotechnology) in the block solution for 2 hours at room temperature. They were washed three times for 5 min with PBS/Tween 20 (0.1%), covered with FITC-labeled secondary antibody to rabbit (4 µg/ml) (Jackson ImmunoResearch Laboratories) in the block solution for 1 hour at room temperature, washed for 5 min with PBS/Tween 20 (0.1%), covered with 4'-6' diamino-2-phenylindole (DAPI) (0.5 µg/ml) for 1 min, and then washed three times for 15 min with the PBS/Tween. Finally, the sections were mounted in a solution of phenylene diamine (PDA) (0.1 mg/ml), DAPI (0.5 µg/ml), and 90% glycerol and photographed on a Zeiss Axioplan fluorescent microscope.

13. This was done by de novo-generated P-element transpositions with a fly stock carrying the P[ry+, 2-3](99B) transposase (40) and an X-linked enhancer/promoter (EP) insert containing 14 UAS sequences in tandem, followed by the Hsp70 heat shock minimal promoter (pEP plasmid) (41). Transposition lines were generated by mobilizing the X-linked P element in the EP55 strain and isolating lines containing new autosomal insertions.

14. For candidate strains, the responsible chromosomes were separated from those carrying GMR-GAL4 or UAS-127Q by crossing with flies that carried the second and third balancer chromosomes CyO and TM3. Their progeny were then crossed to w1118

flies to separate the P elements, and the established strains were tested for suppression or enhancement.

15. Plasmid rescue (39) was done by purifying genomic DNA with the QIAamp Tissue kit (Qiagen, Valencia, CA) and digestion with six restriction enzymes: Bfr I, Bgl I, Eco RI, Hinc II, Sac I, and Sac II in a 100-µl reaction volume overnight. The digested fragments were purified by the QIAprep Spin Miniprep kit (Qiagen), circularized by ligation in a 50-µl reaction volume, and transformed by electroporation of 1.5 µl of ligation reaction into the DH10B strain of E. coli (Gibco/BRL). Bacteria were plated on agar and kanamycin (10 µg/ml). Inserts were sequenced and sequence comparison was done with the BLAST server at BDGP. The protein alignments were done with MacVector 6.0 software.

16. The clone was purchased from Research Genetics, Huntsville, AL. 17. The GenBank accession number is U34904. For consistency, we have changed the

original name, DROJ1 (for Drosophila melanogaster DnaJ homolog) to dHDJ1 (for Drosophila homolog of HDJ1).

18. T. Raabe and J. L. Manley, Nucleic Acids Res. 19, 6645 (1991) [ Free   Full   Text] . 19. M. Hata, K. Okumura, M. Seto, K. Ohtsuka, Genomics 38, 446 (1996) [CrossRef]

[ISI] [Medline] . 20. The GenBank accession number is AF199022. 21. A. E. Murthy, A. Bernards, D. Church, J. Wasmuth, J. F. Gusella, DNA and Cell

Biology 15, 727 (1996) [ISI] [Medline] . 22. The Pst I-Xho I fragment contained a 106-bp Pst I-Eco RI fragment of pOT2a, 11 bp

upstream of the reported 5' UTR; the 5' UTR; the 1005-bp dhdJ1 ORF; 406 bp of the 579-bp reported 3' UTR; and a 23-bp-long polyadenlyate. It was removed from GH26396, contained in the plasmid pOT2a (Research Genetics), and ligated into the transgenic vector pINDY6 Pst I-Xho I site. For cloning dtpr2, the Pst I-Xho I fragment, containing a 106-bp Pst I-Eco RI fragment of pOT2a, the 365-bp 5' UTR, the 1527-bp dtpr2 ORF, the 328-bp 3' UTR, and a 20-bp-long polyadenlyate was removed from GH09432 (within pOT2a) and ligated into the transgenic vector pINDY6 Pst I-Xho I site.

23. W. L. Kelley, Trends Biochem. Sci. 23, 222 (1998) [CrossRef] [ISI] [Medline] . 24. B. Misselwitz, O. Staeck, T. A. Rapoport, Mol. Cell 2, 593 (1998) [CrossRef] [ISI]

[Medline] . 25. D. M. Cyr, T. Langer, M. G. Douglas, Trends Biochem. Sci. 19, 176 (1994)

[CrossRef] [ISI] [Medline] . 26. T. Langer, et al., Nature 356, 683 (1992) [CrossRef] [Medline] . 27. H. Stubdal, et al., Mol. Cell. Biol. 17, 4979 (1997) [Abstract] . 28. M. R. Groves and D. Barford, Curr. Opin. Struct. Biol. 9, 383 (1999) [CrossRef] [ISI]

[Medline] . 29. J. R. Lamb, S. Tugendreich, P. Hieter, Trends Biochem. Sci. 20, 257 (1995)

[CrossRef] [ISI] [Medline] . 30. B. Weiss, G. Bollag, K. Shannon, Am. J. Med. Genet. 89, 14 (1999) [ISI] [Medline] . 31. I. The, et al., Science 276, 791 (1997) [Abstract/ Free   Full   Text] . 32. A. Bergmann, J. Agapite, K. McCall, H. Steller, Cell 95, 331 (1998) [CrossRef] [ISI]

[Medline] . 33. C. J. Cummings, et al., Nature Genet. 19, 148 (1998) [CrossRef] [ISI] [Medline] . 34. D. L. Stenoien, et al., Hum. Mol. Genet. 8, 731 (1999) [Abstract/ Free   Full   Text] . 35. C. Q. Doe, Q. Chu-LaGraff, D. M. Wright, M. P. Scott, Cell 65, 451 (1991)

[CrossRef] [ISI] [Medline] . 36. L. Seroude and S. Benzer, unpublished material.

37. Single-letter abbreviations for the amino acid residues are as follows: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.

38. A. C. Spradling and G. M. Rubin, Science 218, 341 (1982) [Abstract/ Free   Full   Text] . 39. V. Pirrotta, Cloning Drosophila Genes: A Practical Approach, D. B. Roberts, Ed.

(IRL, Oxford, Washington DC, 1986), pp. 83-110. 40. H. M. Robertson, et al., Genetics 118, 461 (1988) [Abstract/ Free   Full   Text] . 41. P. Rorth, Proc. Natl. Acad. Sci. U.S.A. 93, 12418 (1996) [Abstract/ Free   Full   Text] . 42. We thank C. Q. Doe for the gift of prospero cDNA clone p139cAC1; L. Seroude for

the transgenic vector; and V. Sapin, R. Young, and A. Gomez for invaluable technical support. Supported by a Cure HD Initiative postdoctoral fellowship from the Hereditary Disease Foundation and a grant from the Wills Foundation to P.K.-E. and by grants to S.B. from NSF, NIH, and the James G. Boswell Foundation.

2 November 1999; accepted 24 January 2000

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M. Fujimoto, E. Takaki, T. Hayashi, Y. Kitaura, Y. Tanaka, S. Inouye, and A. Nakai (2005)J. Biol. Chem. 280, 34908-34916  |  Abstract »  |  Full Text »  |  PDF »

CHIP Suppresses Polyglutamine Aggregation and Toxicity In Vitro and In Vivo.V. M. Miller, R. F. Nelson, C. M. Gouvion, A. Williams, E. Rodriguez-Lebron, S. Q. Harper, B. L. Davidson, M. R. Rebagliati, and H. L. Paulson (2005)J. Neurosci. 25, 9152-9161  |  Abstract »  |  Full Text »  |  PDF »

Drosophila: A "Model" Model System To Study Neurodegeneration.A. M. Celotto and M. J. Palladino (2005)Mol. Interv. 5, 292-303  |  Abstract »  |  Full Text »  |  PDF »

Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies.

W. J. Wolfgang, T. W. Miller, J. M. Webster, J. S. Huston, L. M. Thompson, J. L. Marsh, and A. Messer (2005)PNAS 102, 11563-11568  |  Abstract »  |  Full Text »  |  PDF »

cAMP-response element-binding protein and heat-shock protein 70 additively suppress polyglutamine-mediated toxicity in Drosophila.

K. Iijima-Ando, P. Wu, E. A. Drier, K. Iijima, and J. C. P. Yin (2005)PNAS 102, 10261-10266  |  Abstract »  |  Full Text »  |  PDF »

Chaperone proteins and brain tumors: Potential targets and possible therapeutics.M. W. Graner and D. D. Bigner (2005)Neuro-oncol 7, 260-278  |  Abstract »  |  PDF »

Modulation of Prion-dependent Polyglutamine Aggregation and Toxicity by Chaperone Proteins in the Yeast Model.

K. C. Gokhale, G. P. Newnam, M. Y. Sherman, and Y. O. Chernoff (2005)J. Biol. Chem. 280, 22809-22818  |  Abstract »  |  Full Text »  |  PDF »

Cardiac Systems Biology.A. D. MCCULLOCH and G. PATERNOSTRO (2005)Ann. N.Y. Acad. Sci. 1047, 283-295  |  Abstract »  |  Full Text »  |  PDF »

The pathogenic agent in Drosophila models of 'polyglutamine' diseases.C. J. McLeod, L. V. O'Keefe, and R. I. Richards (2005)Hum. Mol. Genet. 14, 1041-1048  |  Abstract »  |  Full Text »  |  PDF »

Hsp70 and Hsp40 Chaperones Do Not Modulate Retinal Phenotype in SCA7 Mice.D. Helmlinger, J. Bonnet, J.-L. Mandel, Y. Trottier, and D. Devys (2004)J. Biol. Chem. 279, 55969-55977  |  Abstract »  |  Full Text »  |  PDF »

Trinucleotide repeats and neurodegenerative disease.C. M. Everett and N. W. Wood (2004)Brain 127, 2385-2405  |  Abstract »  |  Full Text »  |  PDF »

Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases.

S. Ghosh and M. B. Feany (2004)Hum. Mol. Genet. 13, 2011-2018  |  Abstract »  |  Full Text »  |  PDF »

Multiple-stress analysis for isolation of Drosophila longevity genes.H.-D. Wang, P. Kazemi-Esfarjani, and S. Benzer (2004)PNAS 101, 12610-12615  |  Abstract »  |  Full Text »  |  PDF »

Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach.

D. G. Hay, K. Sathasivam, S. Tobaben, B. Stahl, M. Marber, R. Mestril, A. Mahal, D. L. Smith, B. Woodman, and G. P. Bates (2004)Hum. Mol. Genet. 13, 1389-1405  |  Abstract »  |  Full Text »  |  PDF »

From The Cover: Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation.

E. A. A. Nollen, S. M. Garcia, G. van Haaften, S. Kim, A. Chavez, R. I. Morimoto, and R. H. A. Plasterk (2004)PNAS 101, 6403-6408  |  Abstract »  |  Full Text »  |  PDF »

Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors.

C.-C. Tsai, H.-Y. Kao, A. Mitzutani, E. Banayo, H. Rajan, M. McKeown, and R. M. Evans (2004)PNAS 101, 4047-4052  |  Abstract »  |  Full Text »  |  PDF »

Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease.

W.-C. M. Lee, M. Yoshihara, and J. T. Littleton (2004)PNAS 101, 3224-3229  |  Abstract »  |  Full Text »  |  PDF »

Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed {beta}-Amyloid in Neurons.

J. Magrane, R. C. Smith, K. Walsh, and H. W. Querfurth (2004)J. Neurosci. 24, 1700-1706  |  Abstract »  |  Full Text »  |  PDF »

Yeast Genes That Enhance the Toxicity of a Mutant Huntingtin Fragment or {alpha}-Synuclein.

S. Willingham, T. F. Outeiro, M. J. DeVit, S. L. Lindquist, and P. J. Muchowski (2003)Science 302, 1769-1772  |  Abstract »  |  Full Text »  |  PDF »

Crystal Structures of Human DJ-1 and Escherichia coli Hsp31, Which Share an Evolutionarily Conserved Domain.

S.-J. Lee, S. J. Kim, I.-K. Kim, J. Ko, C.-S. Jeong, G.-H. Kim, C. Park, S.-O. Kang, P.-G. Suh, H.-S. Lee, et al. (2003)J. Biol. Chem. 278, 44552-44559  |  Abstract »  |  Full Text »  |  PDF »

Cytoplasmic Accumulation of the Nuclear Receptor CAR by a Tetratricopeptide Repeat Protein in HepG2 Cells.

K. Kobayashi, T. Sueyoshi, K. Inoue, R. Moore, and M. Negishi (2003)Mol. Pharmacol. 64, 1069-1075  |  Abstract »  |  Full Text »  |  PDF »

Genetic Modifiers of Tauopathy in Drosophila.J. M. Shulman and M. B. Feany (2003)Genetics 165, 1233-1242  |  Abstract »  |  Full Text »  |  PDF »

Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy.

A. Abu-Baker, C. Messaed, J. Laganiere, C. Gaspar, B. Brais, and G. A. Rouleau (2003)Hum. Mol. Genet. 12, 2609-2623  |  Abstract »  |  Full Text »  |  PDF »

Pathogenesis of polyglutamine disorders: aggregation revisited.A. Michalik and C. Van Broeckhoven (2003)Hum. Mol. Genet. 12, R173-186  |  Abstract »  |  Full Text »  |  PDF »

Fly models of Huntington's disease.J. L. Marsh, J. Pallos, and L. M. Thompson (2003)Hum. Mol. Genet. 12, R187-193  |  Abstract »  |  Full Text »  |  PDF »

Integrative Physiology and Functional Genomics of Epithelial Function in a Genetic Model Organism.

J. A. T. DOW and S. A. DAVIES (2003)Physiol Rev 83, 687-729  |  Abstract »  |  Full Text »  |  PDF »

Hsp105{alpha} Suppresses the Aggregation of Truncated Androgen Receptor with Expanded CAG Repeats and Cell Toxicity.

K. Ishihara, N. Yamagishi, Y. Saito, H. Adachi, Y. Kobayashi, G. Sobue, K. Ohtsuka, and T. Hatayama (2003)J. Biol. Chem. 278, 25143-25150  |  Abstract »  |  Full Text »  |  PDF »

Polyglutamine protein aggregation and toxicity are linked to the cellular stress response.K.J. Cowan, M.I. Diamond, and W.J. Welch (2003)Hum. Mol. Genet. 12, 1377-1391  |  Abstract »  |  Full Text »  |  PDF »

Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein.

J. P. Taylor, A. A. Taye, C. Campbell, P. Kazemi-Esfarjani, K. H. Fischbeck, and K.-T. Min (2003)Genes & Dev. 17, 1463-1468  |  Abstract »  |  Full Text »  |  PDF »

Yeast, Flies, Worms, and Fish in the Study of Human Disease.I. K. Hariharan and D. A. Haber (2003)N. Engl. J. Med. 348, 2457-2463  |  Full Text »  |  PDF »

Parkin Facilitates the Elimination of Expanded Polyglutamine Proteins and Leads to Preservation of Proteasome Function.

Y. C. Tsai, P. S. Fishman, N. V. Thakor, and G. A. Oyler (2003)J. Biol. Chem. 278, 22044-22055  |  Abstract »  |  Full Text »  |  PDF »

Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila.

Y. Nagai, N. Fujikake, K. Ohno, H. Higashiyama, H. A. Popiel, J. Rahadian, M. Yamaguchi, W. J. Strittmatter, J. R. Burke, and T. Toda (2003)Hum. Mol. Genet. 12, 1253-1259  |  Abstract »  |  Full Text »  |  PDF »

A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila.

B. L. Apostol, A. Kazantsev, S. Raffioni, K. Illes, J. Pallos, L. Bodai, N. Slepko, J. E. Bear, F. B. Gertler, S. Hersch, et al. (2003)PNAS 100, 5950-5955  |  Abstract »  |  Full Text »  |  PDF »

blue cheese Mutations Define a Novel, Conserved Gene Involved in Progressive Neural Degeneration.

K. D. Finley, P. T. Edeen, R. C. Cumming, M. D. Mardahl-Dumesnil, B. J. Taylor, M. H. Rodriguez, C. E. Hwang, M. Benedetti, and M. McKeown (2003)J. Neurosci. 23, 1254-1264  |  Abstract »  |  Full Text »  |  PDF »

Suppression of polyglutamine-induced protein aggregation in Caenorhabditis elegans by torsin proteins.

G. A. Caldwell, S. Cao, E. G. Sexton, C. C. Gelwix, J. P. Bevel, and K. A. Caldwell (2003)Hum. Mol. Genet. 12, 307-319  |  Abstract »  |  Full Text »  |  PDF »

Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from huntingtin polyglutamine neurotoxicity.

P. W. Faber, C. Voisine, D. C. King, E. A. Bates, and A. C. Hart (2002)PNAS 99, 17131-17136  |  Abstract »  |  Full Text »  |  PDF »

Golgi Fragmentation Occurs in the Cells with Prefibrillar alpha -Synuclein Aggregates and Precedes the Formation of Fibrillar Inclusion.

N. Gosavi, H.-J. Lee, J. S. Lee, S. Patel, and S.-J. Lee (2002)J. Biol. Chem. 277, 48984-48992  |  Abstract »  |  Full Text »  |  PDF »

Essential Role for the SMN Complex in the Specificity of snRNP Assembly.L. Pellizzoni, J. Yong, and G. Dreyfuss (2002)Science 298, 1775-1779  |  Abstract »  |  Full Text »  |  PDF »

Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila.H.Y. E. Chan, J. M. Warrick, I. Andriola, D. Merry, and N. M. Bonini (2002)Hum. Mol. Genet. 11, 2895-2904  |  Abstract »  |  Full Text »  |  PDF »

Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells.W. Yang, J. R. Dunlap, R. B. Andrews, and R. Wetzel (2002)Hum. Mol. Genet. 11, 2905-2917  |  Abstract »  |  Full Text »  |  PDF »

Suppression of polyglutamine toxicity by a Drosophila homolog of myeloid leukemia factor 1.

P. Kazemi-Esfarjani and S. Benzer (2002)Hum. Mol. Genet. 11, 2657-2672  |  Abstract »  |  Full Text »  |  PDF »

Huntington's disease age-of-onset linked to polyglutamine aggregation nucleation.S. Chen, F. A. Ferrone, and R. Wetzel (2002)PNAS 99, 11884-11889  |  Abstract »  |  Full Text »  |  PDF »

A mouse model of spinal and bulbar muscular atrophy.P. McManamny, H. S. Chy, D. I. Finkelstein, R. G. Craythorn, P. J. Crack, I. Kola, S. S. Cheema, M. K. Horne, N. G. Wreford, M. K. O'Bryan, et al. (2002)Hum. Mol. Genet. 11, 2103-2111  |  Abstract »  |  Full Text »  |  PDF »

Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor.

A. P. Lieberman, G. Harmison, A. D. Strand, J. M. Olson, and K. H. Fischbeck (2002)Hum. Mol. Genet. 11, 1967-1976  |  Abstract »  |  Full Text »  |  PDF »

Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis.

Y. Chai, J. Shao, V. M. Miller, A. Williams, and H. L. Paulson (2002)PNAS 99, 9310-9315  |  Abstract »  |  Full Text »  |  PDF »

Temperature-Sensitive Paralytic Mutants Are Enriched For Those Causing Neurodegeneration in Drosophila.

M. J. Palladino, T. J. Hadley, and B. Ganetzky (2002)Genetics 161, 1197-1208  |  Abstract »  |  Full Text »  |  PDF »

Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1.

A. B. Meriin, X. Zhang, X. He, G. P. Newnam, Y. O. Chernoff, and M. Y. Sherman (2002)J. Cell Biol. 157, 997-1004  |  Abstract »  |  Full Text »  |  PDF »

Transmission of proteotoxicity across cellular compartments.T. Yoneda, F. Urano, and D. Ron (2002)Genes & Dev. 16, 1307-1313  |  Full Text »  |  PDF »

ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats.

H. Nishitoh, A. Matsuzawa, K. Tobiume, K. Saegusa, K. Takeda, K. Inoue, S. Hori, A. Kakizuka, and H. Ichijo (2002)Genes & Dev. 16, 1345-1355  |  Abstract »  |  Full Text »  |  PDF »

Characterization of a Brain-enriched Chaperone, MRJ, That Inhibits Huntingtin Aggregation and Toxicity Independently.

J.-Z. Chuang, H. Zhou, M. Zhu, S.-H. Li, X.-J. Li, and C.-H. Sung (2002)J. Biol. Chem. 277, 19831-19838  |  Abstract »  |  Full Text »  |  PDF »

Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin.

A. Wyttenbach, O. Sauvageot, J. Carmichael, C. Diaz-Latoud, A.-P. Arrigo, and D. C. Rubinsztein (2002)Hum. Mol. Genet. 11, 1137-1151  |  Abstract »  |  Full Text »  |  PDF »

Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice.

Z.-X. Yu, S.-H. Li, H.-P. Nguyen, and X.-J. Li (2002)Hum. Mol. Genet. 11, 905-914  |  Abstract »  |  Full Text »  |  PDF »

Molecular Chaperones in the Cytosol: from Nascent Chain to Folded Protein.F. U. Hartl and M. Hayer-Hartl (2002)Science 295, 1852-1858  |  Abstract »  |  Full Text »  |  PDF »

Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy.

C. K. Bailey, I. F. M. Andriola, H. H. Kampinga, and D. E. Merry (2002)Hum. Mol. Genet. 11, 515-523  |  Abstract »  |  Full Text »  |  PDF »

Alpha1-Antitrypsin Deficiency -- A Model for Conformational Diseases.R. W. Carrell and D. A. Lomas (2002)N. Engl. J. Med. 346, 45-53  |  Full Text »  |  PDF »

Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference.

N. J. Caplen, J. P. Taylor, V. S. Statham, F. Tanaka, A. Fire, and R. A. Morgan (2002)Hum. Mol. Genet. 11, 175-184  |  Abstract »  |  Full Text »  |  PDF »

Chaperone Suppression of Cellular Toxicity of Huntingtin Is Independent of Polyglutamine Aggregation.

H. Zhou, S.-H. Li, and X.-J. Li (2001)J. Biol. Chem. 276, 48417-48424  |  Abstract »  |  Full Text »  |  PDF »

Glucocorticoid modulation of androgen receptor nuclear aggregation and cellular toxicity is associated with distinct forms of soluble expanded polyglutamine protein.

W. J. Welch and M. I. Diamond (2001)Hum. Mol. Genet. 10, 3063-3074  |  Abstract »  |  Full Text »  |  PDF »

Huntingtin Aggregate-Associated Axonal Degeneration is an Early Pathological Event in Huntington's Disease Mice.

H. Li, S.-H. Li, Z.-X. Yu, P. Shelbourne, and X.-J. Li (2001)J. Neurosci. 21, 8473-8481  |  Abstract »  |  Full Text »  |  PDF »

Sequence Analysis of the Human Genome: Implications for the Understanding of Nervous System Function and Disease.

A. Cravchik, G. Subramanian, S. Broder, and J. C. Venter (2001)Arch Neurol 58, 1772-1778  |  Abstract »  |  Full Text »  |  PDF »

Altered transcription in yeast expressing expanded polyglutamine.

R. E. Hughes, R. S. Lo, C. Davis, A. D. Strand, C. L. Neal, J. M. Olson, and S. Fields (2001)PNAS  |  Abstract »  |  Full Text »  |  PDF »

Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death.

J. A. Parker, J. B. Connolly, C. Wellington, M. Hayden, J. Dausset, and C. Neri (2001)PNAS  |  Abstract »  |  Full Text »  |  PDF »

SCA1 molecular genetics: a history of a 13 year collaboration against glutamines.H. T. Orr and H. Y. Zoghbi (2001)Hum. Mol. Genet. 10, 2307-2311  |  Abstract »  |  Full Text »  |  PDF »

Mechanism of Prion Loss after Hsp104 Inactivation in Yeast.R. D. Wegrzyn, K. Bapat, G. P. Newnam, A. D. Zink, and Y. O. Chernoff (2001)Mol. Cell. Biol. 21, 4656-4669  |  Abstract »  |  Full Text »  |  PDF »

Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice.

C. J. Cummings, Y. Sun, P. Opal, B. Antalffy, R. Mestril, H. T. Orr, W. H. Dillmann, and H. Y. Zoghbi (2001)Hum. Mol. Genet. 10, 1511-1518  |  Abstract »  |  Full Text »  |  PDF »

Intracellular Aggregation of Polypeptides with Expanded Polyglutamine Domain Is Stimulated by Stress-activated Kinase MEKK1.

A. B. Meriin, K. Mabuchi, V. L. Gabai, J. A. Yaglom, A. Kazantsev, and M. Y. Sherman (2001)J. Cell Biol. 153, 851-864  |  Abstract »  |  Full Text »  |  PDF »

Beyond the Qs in the polyglutamine diseases.H. T. Orr (2001)Genes & Dev. 15, 925-932  |  Full Text »

The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis.

S. Holbert, I. Denghien, T. Kiechle, A. Rosenblatt, C. Wellington, M. R. Hayden, R. L. Margolis, C. A. Ross, J. Dausset, R. J. Ferrante, et al. (2001)PNAS  |  Abstract »  |  Full Text »

Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila.

H.Y. E. Chan, J. M. Warrick, G. L. Gray-Board, H. L. Paulson, and N. M. Bonini (2000)Hum. Mol. Genet. 9, 2811-2820  |  Abstract »  |  Full Text »  |  PDF »

Polyglutamine disease and neuronal cell death.H. L. Paulson, N. M. Bonini, and K. A. Roth (2000)PNAS  |  Full Text »

Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice.

G. Yvert, K. S. Lindenberg, S. Picaud, G. B. Landwehrmeyer, J.-A. Sahel, and J.-L. Mandel (2000)Hum. Mol. Genet. 9, 2491-2506  |  Abstract »  |  Full Text »  |  PDF »

A Survey of Human Disease Gene Counterparts in the Drosophila Genome.M. E. Fortini, M. P. Skupski, M. S. Boguski, and I. K. Hariharan (2000)J. Cell Biol. 150, F23-F30  |  Abstract »  |  Full Text »  |  PDF »

Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils.

P. J. Muchowski, G. Schaffar, A. Sittler, E. E. Wanker, M. K. Hayer-Hartl, and F. U. Hartl (2000)PNAS  |  Abstract »  |  Full Text »

Involvement of T-complex Protein-1delta in Dopamine Triggered Apoptosis in Chick Embryo Sympathetic Neurons.

R. Zilkha-Falb, A. Barzilai, R. Djaldeti, I. Ziv, E. Melamed, and A. Shirvan (2000)J. Biol. Chem. 275, 36380-36387  |  Abstract »  |  Full Text »  |  PDF »

Requirement of an intact microtubule cytoskeleton for aggregation and inclusion body formation by a mutant huntingtin fragment.

P. J. Muchowski, K. Ning, C. D'Souza-Schorey, and S. Fields (2002)PNAS 99, 727-732  |  Abstract »  |  Full Text »  |  PDF »

The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis.

S. Holbert, I. Denghien, T. Kiechle, A. Rosenblatt, C. Wellington, M. R. Hayden, R. L. Margolis, C. A. Ross, J. Dausset, R. J. Ferrante, et al. (2001)PNAS 98, 1811-1816  |  Abstract »  |  Full Text »  |  PDF »

Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans.S. H. Satyal, E. Schmidt, K. Kitagawa, N. Sondheimer, S. Lindquist, J. M. Kramer, and R. I. Morimoto (2000)PNAS 97, 5750-5755  |  Abstract »  |  Full Text »  |  PDF »

Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils.

P. J. Muchowski, G. Schaffar, A. Sittler, E. E. Wanker, M. K. Hayer-Hartl, and F. U. Hartl (2000)PNAS 97, 7841-7846  |  Abstract »  |  Full Text »  |  PDF »

Altered transcription in yeast expressing expanded polyglutamine.R. E. Hughes, R. S. Lo, C. Davis, A. D. Strand, C. L. Neal, J. M. Olson, and S. Fields (2001)PNAS 98, 13201-13206  |  Abstract »  |  Full Text »  |  PDF »

Polyglutamine disease and neuronal cell death.

H. L. Paulson, N. M. Bonini, and K. A. Roth (2000)PNAS 97, 12957-12958  |  Full Text »  |  PDF »

Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death.

J. A. Parker, J. B. Connolly, C. Wellington, M. Hayden, J. Dausset, and C. Neri (2001)PNAS 98, 13318-13323  |  Abstract »  |  Full Text »  |  PDF »

Age-Associated Cardiac Dysfunction in Drosophila melanogaster.G. Paternostro, C. Vignola, D.-U. Bartsch, J. H. Omens, A. D. McCulloch, and J. C. Reed (2001)Circ. Res. 88, 1053-1058  |  Abstract »  |  Full Text »