Genetic Suppression
Drosophila
of
Polyglutamine
Toxicity
in
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 UASdtpr2 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 proteasomedependent 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
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579-bp reported 3' UTR; and a 23-bp-long polyadenlyate. It was removed from
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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.
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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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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
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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.
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88,
1053-1058
| Abstract » | Full Text »