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General Information
Symbol
Hsap\HTTQ93.ex1.UAS
Species
H. sapiens
Name
FlyBase ID
FBal0127292
Feature type
allele
Associated gene
Associated Insertion(s)
Carried in Construct
Also Known As
UAS-Httex1p Q93, Httex1p Q93, UAS-htt exon-1-Q93, UAS-Httex1p-Q93, P{UAS-Httex1p Q93}, Htt93Q, Httex1-93Q, UASHTT-EX1-PQ93, HttEx1Q93, UAS HTT93Q exon 1
Allele class
Nature of the Allele
Allele class
Mutations Mapped to the Genome
 
Type
Location
Additional Notes
References
Associated Sequence Data
DNA sequence
Protein sequence
 
 
Progenitor genotype
Carried in construct
Cytology
Nature of the lesion
Statement
Reference
UASt sequences drive expression of Hsap\HTT exon 1 with an extended polyglutamine repeat of 93 residues.
Allele components
Product class / Tool use(s)
Encoded product / tool
Expression Data
Reporter Expression
Additional Information
Statement
Reference
 
Marker for
Reflects expression of
Reporter construct used in assay
Human Disease Associations
Disease Ontology (DO) Annotations
Models Based on Experimental Evidence ( 1 )
Modifiers Based on Experimental Evidence ( 1 )
Disease
Interaction
References
is ameliorated by wg1
is ameliorated by wgSp-1
is ameliorated by Wnt2O
is ameliorated by arm3
is ameliorated by pan3
is ameliorated by armG0192
is ameliorated by Wnt2I
is ameliorated by Wnt2RJ
is ameliorated by pan2
is ameliorated by Apc2UAS.cUa
is ameliorated by AxnUAS.cUa
is exacerbated by sggUAS.cBa
is exacerbated by sggS9A.UAS
is ameliorated by ZwUAS.cLa
is ameliorated by PfkUAS.cTa
is ameliorated by jpUAS
is exacerbated by jpKK107921
is ameliorated by Sirt117
is exacerbated by Sirt117
is ameliorated by htt81aa.UAS
is ameliorated by cd1
is ameliorated by cn3
is ameliorated by vKK108195
is ameliorated by v36f
is exacerbated by htt98E2
is ameliorated by BmcpUAS.cBa
is exacerbated by ATP7GD3322
is ameliorated by PsaUAS.cSa
is exacerbated by Drp1UAS.cDa
is exacerbated by Glut117J
is ameliorated by gEP514
is ameliorated by svrEP356
is ameliorated by MESR4EP386
is exacerbated by TlEP1051
is exacerbated by SNF4AγEP3015b
is exacerbated by SNF4AγKG10152
is ameliorated by mubEP3108
is exacerbated by Gcn5E333st
is NOT ameliorated by Gcn5UAS.cBa
is exacerbated by nej3
is NOT exacerbated by mof2
is NOT exacerbated by enok2
Comments on Models/Modifiers Based on Experimental Evidence ( 1 )
 
The progressive degeneration seen in Hsap\HTTQ93.ex1p.Scer\UAS flies is significantly relieved when flies are fed the C2-8 compound.
Phenotypic Data
Phenotypic Class
Phenotype Manifest In
Detailed Description
Statement
Reference
Flies expressing Hsap\HTTQ93.ex1.Scer\UAS under the control of Scer\GAL4GMR.PU have normal external morphology of the eye at day 1 post-eclosion but suffer progressive degeneration of the underlying retina resulting in patchy depigmentation as the flies age.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 results in adult weight alteration, as measured by fresh weight, dry weight and water content, with a small but significant decrease in weight at 0 days post eclosion, significantly increased weight at 3-9 days, no significant difference in weight at 11 days, and decreased weight at 13 days post-eclosion, as compared to controls. These flies do not survive beyond day 13 post eclosion. As compared to controls, flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 also exhibit arrhythmic feeding; significantly increased levels of trehalose and glycogen at 3 and 5 days, but not at 0, 7, 9, 11, or 13 days post-eclosion; significantly increased protein content at 7 and 9 days, decreased protein content at 13 days, but no difference at 0, 3, 5, or 11 days post-eclosion; significantly decreased lipid content at 0, 11 and 13 days, significantly increased lipid content at 3, 5, and 7 days, but no significant difference in lipid content 9 days post-eclosion. Lipid droplet size in the larval fat body is unaltered, but lipid droplets in the adult abdominal fat body are increased in size at 3-7 days and decreased in size by day 11-13 post-eclosion. Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4Ilp2.PR in adults results in significantly decreased adult weight at 0, 7 and 13 days, but not at 3, 5, 9 or 11 days post-eclosion; significantly increased lipid content at 5 and 9 days, but not at 0, 3, 7, 11 and 13 days post-eclosion; significantly decreased glycogen content 0, 3 and 7 days, significantly increased glycogen content at 5 and 11 days, but no significant difference at 9 or 13 days post-eclosion; significantly increased trehalose content at 0 and 11 days, significantly decreased trehalose content at 3 and 5 days, but no significant difference at 7, 9 and 13 days post-eclosion. Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4Akh.PL in adults results in significantly decreased adult weight at 5-13 days, but not 0-3 days post-eclosion; significantly decreased lipid content at 0 days, significantly increased at 3, 5, 7 and 11 days, but no significant difference at 9 or 13 days post-eclosion; significantly decreased glycogen at 3 days, significantly increased glycogen content at 5, 6, 11 and 13 days, but no significant difference at 0 or 9 days post-eclosion; significantly increased trehalose content at 0-5 days, significantly decreased trehalose content at 11 days, but no significant difference at 7, 9 or 13 days post-eclosion.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 result in photoreceptor neurodegeneration in the adult eye at 7 days post-eclosion and reduced crawling ability in third instar larvae; expression under Scer\GAL4GMR.PF induces an age-progressive rough eye phenotype.
Compared with wild-type, expression of Hsap\HTTQ93.ex1p.Scer\UAS in neuronal cells using Scer\GAL4elav-C155 reduces fly longevity. Flies expressing Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS display defects in their negative geotaxis response. Expression of Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS leads to an obvious loss of one or more photoreceptors leading to a disorganization of ommatidia. 6-day old flies expressing Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS are insensitive to oxidative stress generated by hydrogen peroxide treatment. It is noteworthy, that these flies do not yet present pathological symptoms.
The end-systolic diameter (ESD) and end-diastolic diameter (EDD) of 5-day old flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4Hand.ΔVM.Switch (limited to the adult stages using 100ug/ml RU486) are similar to controls. No significant changes are seen in the ESD at 19 days, but the EDD is modestly but significantly increased. When flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4Hand.ΔVM.Switch are raised on medium containing 2ug/ml RU486 adults are produced adults are produced but the hearts are severely impaired. When raised on a lower RU485 concentration (20ng/ml) the flies could be seen to have dilated hearts, with increases in ESD and EDD that are more severe than those seen when expression is limited to adulthood. Feeding the flies Methylene blue along with RU486 significantly rescues the heart dilatation at 19 days. Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS either in neurons under the control of Scer\GAL4Appl.PU or in glia under the control of Scer\GAL4repo.PU show a strong deficit in mean lifespan compared to controls. This reduction in lifespan is not rescued by feeding the flies Methylene Blue, and is aggravated when Hsap\HTTQ93.ex1p.Scer\UAS is expressed in neurons.
1-day old flies expressing Scer\GAL4elav.PU>Hsap\HTTQ93.ex1p.Scer\UAS show neurodegeneration in the retina. Neurodegeneration is moderate at this age, although some photoreceptors start to display rhabdomere atrophy or cytoplasmic condensation typical of apoptosis. Non-apoptotic photoreceptors contain two types of mitochondria: typical round-shaped mitochondria, and, unexpectedly, mitochondrial tubules that seem to bend and often fuse at their extremities to adopt a ring-shaped structure. Sometimes those bended mitochondria engulf cytoplasmic components such as pigment granules. 12-day old flies expressing Hsap\HTTQ93.ex1p.Scer\UAS in postmitotic neurons in the central brain display neurodegeneration. About 7% of degenerative neurons show cytoplasmic vacuolization in the olfactory lobes.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 results in a progressive loss of rhabdomeres and photoreceptor cells during their lifespan.
The external eye morphology and vision of freshly-eclosed Scer\GAL4GMR.PU-->Hsap\HTTQ93.ex1p.Scer\UAS flies are near normal. However, these flies show a progressive age-dependent degeneration, becoming almost completely blind by 10 days. The eye surface of these flies do not show any appreciable change with age in any of the feeding regimes. The pseudopupil images of rhabdomeres of 1-day-old Scer\GAL4GMR.PU-->Hsap\HTTQ93.ex1p.Scer\UAS flies fed on a normal diet show severely degenerated rhabdomeres so that, unlike the stereotyped pattern of rhabdomeres in pseudopupil image of eyes of wild-type flies, no distinct rhabdomeres are seen in their eyes. Scer\GAL4GMR.PU-->Hsap\HTTQ93.ex1p.Scer\UAS flies fed on azaserine-supplemented food display at least some organised rhabdomere-like structures in approximately 60% of flies. Scer\GAL4GMR.PU-->Hsap\HTTQ93.ex1p.Scer\UAS flies reared on normal food exhibit a progressive loss of vision such that the proportion of flies selecting the lighted chamber in a phototaxis assay declines with age. By day 10, these flies become nearly blind and move at random between dark and light chambers. Significantly, a greater proportion of Scer\GAL4GMR.PU-->Hsap\HTTQ93.ex1p.Scer\UAS flies reared on azaserine-supplemented food continue to move to the illuminated chamber even on day 15. Thus, azaserine feeding partially restores vision in these flies. Scer\GAL4GMR.PU-driven expression of Hsap\HTTQ93.ex1p.Scer\UAS leads to the accumulation of polyQ inclusion bodies posterior to the morphogenetic furrow in late third instar larval eye discs. Feeding these larvae with azaserine substantially reduces the accumulation of Hsap\HTT aggregates, such that in 57% of eye discs from azaserine-fed larvae, the aggregates are nearly absent behind the morphogenetic furrow, although in the remaining discs immunostaining is less than in the eye discs from larvae fed a normal diet.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PU results in the formation of aggregates in larval eye imaginal discs and subsequent age-dependent retinal degeneration and visual impairment measured by phototaxic response, as compared to wild type. Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU results in climbing defects and a dramatic reduction in lifespan.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS in photoreceptor cells under the control of Scer\GAL4GMR.PF triggers strong neuronal degeneration, with only a small detectable depolarization remaining after 1 week.
Pan-neuronal expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 leads to robust degeneration of photoreceptor neurons.
Animals expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 exhibit loss of retinal neurons and impaired motor function. At 10 microM, selisistat is able to rescue degeneration to at least the same level as genetic loss of one copy of the Sir2 gene.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 results in progressive degeneration of photoreceptor rhabdomeres in the eye. This phenotype can be partially suppressed by feeding the flies ebselen. Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 show reduced locomotor activity compared to wild type. Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4P2.4.Pdf show loss of the small lateral ventral neurons compared to wild type.
Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU show loss of photoreceptor rhabdomeres.
Adults expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU show reduced mobility in a climbing assay. Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PU results in loss of eye pigmentation and progressive loss of rhabdomeres. The survival rate of animals expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU is significantly increased by dietary copper chelation (0.05mM bathocuproine disulfonate) or 0.00625mM clioquinol and is significantly reduced by addition of 0.25mM CuCl[[2]].
Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 results in a reduced eclosion rate.
Larval ddaE neurons expressing Hsap\HTTQ93.ex1.UAS under the control of Scer\GAL4221 show a significant increase in growing microtubules within dendrites, as compared to neurons in controls.
Flies with expression of Hsap\HTTQ93.ex1p.Scer\UAS driven by Scer\GAL4elav.PU or Scer\GAL4Eaat1.PR have a shorter lifespan compared to controls. Scer\GAL4elav.PU>Hsap\HTTQ93.ex1p.Scer\UAS flies have locomotor impairments (significant reduction in climbing performance) and have photoreceptor loss in the ommatidia of the retina. Scer\GAL4repo.PU>Hsap\HTTQ93.ex1p.Scer\UAS flies have locomotor impairments (significant reduction in climbing performance) and more than a third of flies are bang sensitive at 12 days of age. Scer\GAL4repo.PU>Hsap\HTTQ93.ex1p.Scer\UAS flies show normal baseline electrophysiological recordings in response to a single-pulse stimulus in the giant fiber pathway (recording from dorsal longitudinal muscle), but 12 day old flies show significant defects in response to high frequency stimulation (at 200Hz the number of delayed discharges is significantly enhanced and delay discharge timing is significantly delayed).
Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 show reduced evoked excitatory junction potential (eEJP) amplitudes recorded at the third instar larval neuromuscular junction at 0.6 or 1.5 mM Ca[2+] concentrations compared to controls. Miniature excitatory junction potential (mEJP) amplitude is also reduced. mEJP decay kinetics, mEJP frequency, mean resting membrane potential and quantal content are all unaffected. The average synaptic vesicle diameter in larvae expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 is smaller than in controls in both 1s and 1b boutons. NMJ boutons expressing Hsap\HTTQ93.ex1p.Scer\UAS also show increased numbers of vacuoles, multi-lammelar bodies and multivesicular bodies. The number of active zones is comparable to controls. Larvae expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4C164 perform significantly fewer turns than controls in a crawling assay. The distance travelled is also significantly increased.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 results a 2 to 3 fold increase in the 3-hydroxykynurenine (3-HK)/kynurenic acid (KYNA) ratio as compared to controls at day one and day 7 post-eclosion. Treating flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 with the KMO inhibitors UPF648, JM6 or Ro 61-8048 produces suppression of the rhabdomere degeneration seen at seven days post eclosion. 3-hydroxykynurenine (3-HK) feeding significantly potentiates the rhabdomere loss. Conversely feeding the flies with kynurenic acid (KYNA) confers a significant but modest increase in rhabdomere number and an associated reduction in the 3-HK/KYNA ratio.
Expression of Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 results in photoreceptor neuron degeneration, and a decrease in photoreceptor cell number is observed. This phenotype is suppressed in a dose-dependent manner by increasing concentrations of fisetin in the fly food medium, rescuing the number of photoreceptor cells observed in the eye. The number of adult flies surviving to 7-days post-eclosion also increases in a dose-dependent manner in the presence of fisetin.
Pan-neuronal expression of Hsap\HTTQ93.ex1.Scer\UAS, under the control of Scer\GAL4elav-C155 results in some pupal lethality, with approximately 40% of flies emerging as adults. These surviving adults are short lived as compared to controls. Pan-neuronal expression of Hsap\HTTQ93.ex1.Scer\UAS, under the control of Scer\GAL4elav-C155 results in rhabdomere degeneration.
At 12 days post-eclosion, only 26% of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4repo reach the top of a column after a startle and >46% remain at the bottom. This is in contrast to control flies which all reach the top of the column. At 12 days post-eclosion, ~40% of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4repo are bang sensitive. >70% of adult flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4repo are dead at 16 days. Adult flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4Eaat1.PR die early. Only 59% of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 reach the top of a column after a startle. This is in contrast to control flies where 90% reach the top of the column. Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 die early and do not survive beyond 28 days post eclosion. Expression of Hsap\HTTQ93.ex1p.Scer\UAS using Scer\GAL4ey-OK107 results in loss of mushroom body gamma lobes in 12 day old flies, whereas the alpha and beta lobes remain intact.
Adult flies expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 treated continuously wth 100υM cystamine alone over a 6 day period produces a significant 17% rescue of photoreceptors compared to no-drug controls, while treatment with 50 and 250υM doses has no significant effects. In Hsap\HDQ93.ex1p.Scer\UAS-expressing flies expressing the Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 transgene, both under the control of Scer\GAL4elav-C155, photoreceptors are significantly rescued by 48% compared to no intrabody controls. The combination of Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 and postsymptomatic 100υM cystamine treatment rescues 66% of photoreceptors compared to Hsap\HDQ93.ex1p.Scer\UAS controls undergoing neither treatment. Neither the 50&ugrM nor the 250υM cystamine dose combined with the Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 intrabody treatment show any significant difference from intrabody treatment alone. Feeding cystamine throughout larval and adult stages does not affect photoreceptor neurodegeneration in flies expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Feeding of cystamine to adult flies expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 does not significantly improve survival. A higher dose of 250υM produces a small yet significant decrease in survival. Co-expression of Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 produces a significant increase in mean survival, by almost three days. Combination of either a 50υM or 250υM dose of cystamine with Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 expression leads to significantly decreased survival compared to Hsap\HDQ93.ex1p.Scer\UAS-expressing flies co-expressing Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 alone. Combination of Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 expression with 100υM postsymptomatic cystamine treatment does not change survival times compared to Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 expression alone. Treatment of Hsap\HDQ93.ex1p.Scer\UAS expressing flies (under the control of Scer\GAL4elav-C155) presymptomatically with 100υM cystamine at the larval as well as adult stages significantly increases survival, relative to no-drug Hsap\HDQ93.ex1p.Scer\UAS flies. Co-expression of Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 confers significantly improved survival on Hsap\HDQ93.ex1p.Scer\UAS flies. Administration of 50υM or 100υM doses of cystamine at larval and adult stages in Hsap\HDQ93.ex1p.Scer\UAS flies co-expressing Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 results in an additional improvement in survival (this is not seen with a 250υM dose of cystamine).
The expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU results in decreased average rhabdomere number in the adult eye.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS in the brain under the control of Scer\GAL4elav-C155 reduces the lifespan of the mutants relative to wild-type.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PU results in progressive degeneration in the eye.
Expression of Hsap\HDQ93.ex1p.Scer\UAS using Scer\GAL4GMR.PF results in normal ommatidial morphology in freshly emerged flies, but rhabdomere degeneration is seen in 10-day old flies. 10-day old flies expressing Hsap\HDQ93.ex1p.Scer\UAS using Scer\GAL4GMR.PF fail to detect light.
Expression of Hsap\HTTQ93.ex1.Scer\UAS using Scer\GAL4GMR.PF also results in decreased adult lifespan, as compared to controls.
Scer\GAL4elav.PU-mediated expression of Hsap\HTTQ93.ex1p.Scer\UAS leads to a marked disruption of the number as well as the arrangement of rhabdomeres 10 days post-eclosion.
Adults expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 are initially hyperactive and then show a gradual loss of coordination and a decline in locomotor activity. These animals die at around 20 days of age. Progressive degeneration of the photoreceptors is also seen.
Expression with Scer\GAL4GMR.PU causes a rough eye phenotype accompanied by a 'glassy' appearance.
Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PU leads to late-onset eye depigmentation. Expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 disrupts the regular arrangement of the retina, progressively decreasing the number of photoreceptors in each ommatidium as observed by pseudopupil analysis. Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS in neurons under the control of Scer\GAL4elav-C155 die between days 8 and 28 of adult age. A similar phenotype is seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed in glia under the control of Scer\GAL4repo.PU. Lifespan is unaffected when Hsap\HTTQ93.ex1p.Scer\UAS is expressed in the surface or peripheral glia (under the control of Scer\GAL4moody.PS and Scer\GAL4Gli.PS respectively) but expression under the control of Scer\GAL4Eaat1.PR, which expresses in CNS cortex glia and PNS perisynaptic glia, results in lethality as early as 12 days. Adult flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of either Scer\GAL4elav-C155 or Scer\GAL4repo.PU show locomotor defects in a negative geotaxis test. Walking speed is also reduced. Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4repo.PU also exhibit a bang sensitive phenotype. No locomotor defects are seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4Eaat1.PR. Pan-neuronal expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 results in degeneration of the kenyon cells that comprise the γ-lobe of the mushroom body.
Flies expressing Scer\GAL4GMR.PF>Hsap\HTTQ93.ex1p.Scer\UAS display age-dependent eye depigmentation as well as disorganization of ommatidial arrays. The eye pigmentation and ommatidial defects are not observed when Hsap\HTTQ0.Scer\UAS is co-expressed with Hsap\HTTQ93.ex1p.Scer\UAS
Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 do not exhibit changes in lifespan when reared on diluted food (while control flies display increased longevity). There is also no change in photoreceptor neuron survival in these flies. Addition of resveratrol to food fed to flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 can rescue neuronal degeneration in a dose-dependent manner, although it does not alter the early death phenotype of these flies.
Expression of Hsap\HDQ93.ex1p.Scer\UAS in the developing eye disc, under the control of Scer\GAL4GMR.PF results in a loss of pigmentation and disruption of the regular ordered arrays of ommatidia in adult eyes without affecting the eye size.
Five days after overexpression of Hsap\HDQ93.ex1p.Scer\UAS in photoreceptor neurons, under the control of Scer\GAL4ninaE.PD, the protein is found primarily in the cytosol in multiple, small aggregates. Twenty-four hours later, at day 6, nuclear aggregates begin to appear. By day ten, most nuclei contain nuclear inclusions. By as late as 8 days after inclusion, flies expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4ninaE.PD exhibit seven intact rhabdomeres, similar to wild-type flies. By day 12, the average n umber of rhabdomeres per ommatidium decreases to 5.8, indicating mild degeneration.
When Hsap\HDQ93.ex1p.Scer\UAS is driven by Scer\GAL4OK107 changes in the structure of the mushroom body are apparent. The alpha'-lobes and beta'-lobes are mostly missing, the number of fibres in the gamma-lobe is reduced ,and Kenyon cell bodies responsible for these fibres are also reduced. The number of cells in the median bundle cluster is reduced from ~20 to ~8. In addition, the cells of the ventral ganglia show a reduced number of cell bodies and the projections reveal clear dismorphology. Cells in the abdominal region of the ventral ganglia show changes in neuronal morphology with loss of projections and rounded (rather than stellate) shape. When Hsap\HDQ93.ex1p.Scer\UAS is driven by Scer\GAL4elav-C155, an approximately 24% volume reduction is seen the mushroom body 10 days after eclosion.
Flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4Eaat1.PR have a shortened lifespan compared to wild type and are found to be lethargic a few days before dying.
Expression of Hsap\HDQ93.ex1p.Scer\UAS at 25oC, under the regulation of Scer\GAL4elav-C155 results in 23% eclosion from the pupal case. Most Hsap\HDQ93.ex1p.Scer\UAS flies dies as externally normal adults (pharate adults) trapped in the pupal case unable to act out the stereotypic eclosion behaviour required to emerge. Co-expression with Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 rescues survival to 100%. The mean and median survival time for Hsap\HDQ93.ex1p.Scer\UAS flies co-expressing Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1, under the control of Scer\GAL4elav-C155, compared to flies expressing solely Hsap\HDQ93.ex1p.Scer\UAS is increased significantly, with increases ranging from 30% to 50%. Maximum lifespan is also significantly improved, although not to that of wild-type levels. Genetically doubling the dose of Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 produces no further improvement in survival. Co-expression of Hsap\HDD10sFv.Scer\UAS.T:Ivir\HA1 with Hsap\HDQ93.ex1p.Scer\UAS, under the control of Scer\GAL4elav-C155 generates a modest reduction in mean, median, and maximum survival time which is not considered significant. Newly emerged flies expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 reveal numerous visible Hsap\HD aggregates in the cell bodies of optic lobe neurons. Significantly, aggregate density in Hsap\HDQ93.ex1p.Scer\UAS flies is reduced by 44% in the optic lobe lamina when Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 is co-expressed, but is unaffected when Hsap\HDD10sFv.Scer\UAS.T:Ivir\HA1 is co-expressed. This Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1-dependent reduction in aggregate formation is no longer evident in 6-day old flies. Hsap\HDQ93.ex1p.Scer\UAS flies (Scer\GAL4elav-C155) exhibit an age-dependent loss of photoreceptor cells. The percentage of ommatidia that contain seven rhabdomeres, indicating no neurodegeneration, in Hsap\HDQ93.ex1p.Scer\UAS flies expressing Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 is 88%, which is almost double that in Hsap\HDQ93.ex1p.Scer\UAS flies (49%), or in Hsap\HDQ93.ex1p.Scer\UAS flies expressing the control Hsap\HDD10sFv.Scer\UAS.T:Ivir\HA1 (47%). In 1-day old flies where Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 is co-expressed with Hsap\HDQ93.ex1p.Scer\UAS (both under the control of Scer\GAL4elav-C155), ommatidia having fewer than six rhabdomeres are never observed, whereas in flies expressing only Hsap\HDQ93.ex1p.Scer\UAS or Hsap\HDQ93.ex1p.Scer\UAS and the control Hsap\HDD10sFv.Scer\UAS.T:Ivir\HA1 (under the regulation of Scer\GAL4elav-C155) as few as three ommatidia are observed. After 6 days of adult life, Hsap\HDQ93.ex1p.Scer\UAS, Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 flies exhibit a futher loss of photoreceptors. 15% of Hsap\HDQ93.ex1p.Scer\UAS, Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 (Scer\GAL4elav-C155) ommatidia contain seven photoreceptors, three times more than in flies expressing Hsap\HDQ93.ex1p.Scer\UAS either alone (5%) or with the control Hsap\HDD10sFv.Scer\UAS.T:Ivir\HA1 (6%).
Photoreceptor neurons are progressively lost and the integrity of the eye is compromised.
When Hsap\HDQ93.ex1p.Scer\UAS is driven by Scer\GAL4179Y or Scer\GAL4Appl.G1a accumulations of organelles are seen in neurons, characteristic of a defect in axonal transport. When Hsap\HDQ93.ex1p.Scer\UAS is overexpressed in neurons, increased cell death is seen.
Mutant flies have eyes that have reduced numbers of rhabdomeres, caused by progressive neurodegeneration of photoreceptor neurons. Feeding the flies Y-27632 slows the loss of photoreceptor neurons.
When Hsap\HDQ93.ex1p.Scer\UAS is driven by Scer\GAL4elav-C155, a progressive loss of rhabdomeres is seen. Rather than the normal seven visible rhabdomeres, the number progressively declines from an average of 6.35 at day 1 to 5.13 and 4.66 at days 6 and 12 after eclosion respectively. Expression of Hsap\HDQ93.ex1p.Scer\UAS leads to 70% lethality and early adult death. Suberoylanilide hydroxamic acid (SAHA) suppresses the lethality to 45% and reduces the level of degeneration seen in the eye.
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Phenotypic Class
Enhanced by
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NOT Enhanced by
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Hsap\HTTQ93.ex1.UAS, Scer\GAL4elav.PU has short lived phenotype, non-enhanceable by Pink1[+]/Pink1B9
Hsap\HTTQ93.ex1.UAS, Scer\GAL4elav-C155 has short lived | calorie restriction conditional phenotype, non-enhanceable by HDAC3dsRNA.UAS, Scer\GAL4elav-C155
Hsap\HTTQ93.ex1.UAS, Scer\GAL4elav-C155 has short lived | calorie restriction conditional phenotype, non-enhanceable by HDAC4dsRNA.UAS, Scer\GAL4elav-C155
Hsap\HTTQ93.ex1.UAS, Scer\GAL4elav-C155 has short lived | calorie restriction conditional phenotype, non-enhanceable by HDAC11dsRNA.UAS, Scer\GAL4elav-C155
Suppressed by
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NOT suppressed by
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Hsap\HTTQ93.ex1.UAS, Scer\GAL4elav-C155 has lethal phenotype, non-suppressible by rl[+]/rl10a
Hsap\HTTQ93.ex1.UAS, Scer\GAL4elav-C155 has short lived | calorie restriction conditional phenotype, non-suppressible by HDAC3dsRNA.UAS, Scer\GAL4elav-C155
Hsap\HTTQ93.ex1.UAS, Scer\GAL4elav-C155 has short lived | calorie restriction conditional phenotype, non-suppressible by HDAC4dsRNA.UAS, Scer\GAL4elav-C155
Hsap\HTTQ93.ex1.UAS, Scer\GAL4elav-C155 has short lived | calorie restriction conditional phenotype, non-suppressible by HDAC11dsRNA.UAS, Scer\GAL4elav-C155
Hsap\HTTQ93.ex1.UAS, Scer\GAL4elav-C155 has short lived | calorie restriction conditional phenotype, non-suppressible by HDAC15-5/Rpd3[+]
NOT Suppressor of
Other
Phenotype Manifest In
Enhanced by
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NOT Enhanced by
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Hsap\HTTQ93.ex1.UAS, Scer\GAL4GMR.PU has eye phenotype, non-enhanceable by CG2924[+]/CG2924EY02142
Hsap\HTTQ93.ex1.UAS, Scer\GAL4GMR.PU has eye phenotype, non-enhanceable by Sap13006924/l(3)06924[+]
Suppressed by
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Reference
Hsap\HTTQ93.ex1.UAS, Scer\GAL4GMR.PU has eye phenotype, suppressible by ATP7[+]/ATP7EY07895
Hsap\HTTQ93.ex1.UAS, Scer\GAL4GMR.PU has eye phenotype, suppressible by UbcD4[+]/Ubc4EY05497
NOT suppressed by
Statement
Reference
Hsap\HTTQ93.ex1.UAS, Scer\GAL4GMR.PU has eye phenotype, non-suppressible by CG2924[+]/CG2924EY02142
Hsap\HTTQ93.ex1.UAS, Scer\GAL4GMR.PU has eye phenotype, non-suppressible by Sap13006924/l(3)06924[+]
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Xenogenetic Interactions
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The age-progressive retinal degeneration manifested by patchy depigmentation of the adult eye characteristic for flies expressing Hsap\HTTQ93.ex1.Scer\UAS under the control of Scer\GAL4GMR.PU is ameliorated by co-expression of jpUAS and exacerbated by co-expression of jpKK107921.
Co-expression of Hsap\SLC2A3Scer\UAS.cBa extends the lifespan and ameliorates the climbing defects in flies expressing Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS. The disruption of ommatidial arrangements is markedly rescued in flies expressing Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS when Hsap\SLC2A3Scer\UAS.cBa is co-expressed. Overexpression of PfkScer\UAS.cTa under the control of Scer\GAL4elav-C155 does not change the survival of flies also expressing Hsap\HTTQ93.ex1p.Scer\UAS. However, statistical analysis of pseudopupil data shows that PfkScer\UAS.cTa overexpression prevents neurodegeneration at day and day 4. Co-expression of PfkScer\UAS.cTa has no additional effect on the survival or degeneration of photoreceptors in flies co-expressing Hsap\SLC2A3Scer\UAS.cBa and Hsap\HTTQ93.ex1p.Scer\UAS using Scer\GAL4elav-C155. Overexpression of ZwScer\UAS.cLa significantly extends lifespan and suppresses eye photoreceptor neurodegeneration in flies expressing Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS. Overexpression of ZwScer\UAS.cLa does not statistically change the survival of flies co-expressing Hsap\SLC2A3Scer\UAS.cBa and Hsap\HTTQ93.ex1p.Scer\UAS using Scer\GAL4elav-C155. 12 day-old flies co-expressing Hsap\HTTQ93.ex1p.Scer\UAS and ZwScer\UAS.cLa under the control of Scer\GAL4elav-C155 display a significantly enhanced resistance to oxidative stress compared with wild-type. Co-expression of dhdScer\UAS.cUa significantly extends the lifespan of flies expressing Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS. Co-expression of Jafrac1Scer\UAS.cHa significantly extends the lifespan of flies expressing Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS.
Overexpression of Pink1Scer\UAS.T:Ivir\HA1 significantly reduces mitochondrial spheroid formation in photoreceptor neurons. Pseudo-pupil analysis reveal that Pink1Scer\UAS.T:Ivir\HA1 overexpression markedly reduces photoreceptor loss in 1-day-old flies. Overexpression of Pink1Scer\UAS.T:Ivir\HA1 results in the reduction of the number of degenerative neurons showing cytoplasmic vacuolization in the olfactory lobes. Pink1Scer\UAS.T:Ivir\HA1 significantly increases both mean and median survival of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS. Heterozygous Pink1B9 does not decrease life span in flies expressing Scer\GAL4elav.PU>Hsap\HTTQ93.ex1p.Scer\UAS. Overexpression of Pink1Scer\UAS.T:Ivir\HA1 in heterozygous park1 flies which also express Scer\GAL4elav.PU>Hsap\HTTQ93.ex1p.Scer\UAS fails to increase life span. Overexpression of Pink1Scer\UAS.T:Ivir\HA1 in heterozygous park1 flies which also express Scer\GAL4elav.PU>Hsap\HTTQ93.ex1p.Scer\UAS fails to provide protection against photoreceptor degeneration. Overexpression of Drp1Scer\UAS.cDa in flies also expressing Scer\GAL4elav.PU>Hsap\HTTQ93.ex1p.Scer\UAS results in an about 23% further reduction in lifespan. Co-expression of MarfmiRNA.cUa.Scer\UAS results in a significant reduction of Pink1Scer\UAS.T:Ivir\HA1-mediated neuronal rescue in Scer\GAL4elav.PU>Hsap\HTTQ93.ex1p.Scer\UAS flies. Overexpression of Pink1Scer\UAS.T:Ivir\HA1 in the presence of heterozygous porink05123 fails to extend lifespan or suppress neuronal loss in flies also expressing Scer\GAL4elav.PU>Hsap\HTTQ93.ex1p.Scer\UAS.
Co-expression of mavGL01025 ameliorates the rhabdomere and photoreceptor neuron loss seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155.
Co-expression of HsfGD16368 exacerbates the formation of aggregates in the eye disc seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PU.
Knockdown of Acn, through expression of AcnKK111555 under the control of Scer\GAL4GMR.PF enhances the neuronal degeneration and depolarization seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS. In two week-old flies, one copy of Acnt.D527A significantly improves the neuronal depolarization seen in Hsap\HTTQ93.ex1p.Scer\UAS-expressing flies. The build up of aggregates seen in two week-old Hsap\HTTQ93.ex1p.Scer\UAS-expressing flies is reduced by the presence of one copy of Acnt.D527A. The build up of aggregates seen in two week-old Hsap\HTTQ93.ex1p.Scer\UAS-expressing flies is reduced by the presence of one copy of Acnt.S641D.S731D. One copy of Acnt.D527A does not affect the neuronal depolarization seen in 2 week old Hsap\HTTQ93.ex1p.Scer\UAS-expressing flies.
Expression of DJ-1αScer\UAS.cMa suppresses the rhabdomere degeneration seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Expression of dj-1βScer\UAS.cMa suppresses the rhabdomere degeneration seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155.
When Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS-expressing animals are also heterozygous for Sir217, the extent of neuronal loss is reduced and show improved motor function compared with siblings wild type Sir2. However, homozygous Sir217 enhances the neuronal loss phenotype and exacerbates the defects in motor function.
Glut117J does not significantly enhance the rhabdomere loss seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. The reduction in eclosion frequency is significantly enhanced. Expression of Glut1KK108683 enhances the rhabdomere loss and reduction in lifespan seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Expression of Glut1d05758 partially suppresses the rhabdomere loss seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Eclosion rate is not significantly altered compared to expression of Hsap\HTTQ93.ex1p.Scer\UAS alone.
Co-expression of Mmus\Gpx1Scer\UAS.cMa partially suppresses the progressive photoreceptor rhabdomere degeneration seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Co-expression of Mmus\Gpx1Scer\UAS.cMa suppresses the reduced locomotor activity seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Co-expression of Mmus\Gpx1Scer\UAS.cMa completely suppresses the loss of the small lateral ventral neurons seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4P2.4.Pdf.
The loss of rhabdomere phenotype seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU is partially suppressed by lid10424/+.
Co-expression of Ctr1BNIG.7459R partially suppresses the mobility defects of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU. Co-expression of ATP7GD3322 enhances the mobility defects of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU. Co-expression of either Ctr1BNIG.7459R or ATP7EY07895 partially suppresses loss of eye pigmentation and progressive loss of rhabdomeres seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PU. Co-expression of ATP7GD3322 enhances loss of eye pigmentation and progressive loss of rhabdomeres seen in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PU. Co-expression of either ATP7EY07895 or Ctr1BNIG.7459R suppresses the aggregation of Hsap\HTTQ93.ex1p.Scer\UAS protein seen in the brains of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU. Co-expression of ATP7GD3322 enhances the aggregation of Hsap\HTTQ93.ex1p.Scer\UAS protein seen in the brains of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU.
One copy of PcafE333st enhances the reduction in eclosion rate seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. These flies have a relative eclosion rate of 49.4%. PcafE333st/+ also enhances rhabdomere loss, with an average of 4.32 rhabdomeres per ommatidium. One copy of Df(3L)iro-2 enhances the reduction in eclosion rate seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. These flies have a relative eclosion rate of 54%. Df(3L)iro-2/+ also enhances rhabdomere loss, with an average of 4.42 rhabdomeres per ommatidium. One copy of nej3 enhances the reduction in eclosion rate seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. These flies have a relative eclosion rate of 67.3%. One copy of enok2 does not enhance the reduction in eclosion rate seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. One copy of mof2 does not enhance the reduction in eclosion rate seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. One copy of Df(3R)Exel6259 does not enhance the reduction in eclosion rate seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Expression of PcafScer\UAS.cBa does not significantly suppress either the reduction in eclosion rate or the rhabdomere loss seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155.
arm3/+ or armG0192/+ significantly partially suppresses the decreased lifespan seen in flies with expression of Hsap\HTTQ93.ex1p.Scer\UAS driven by Scer\GAL4elav.PU or Scer\GAL4Eaat1.PR. wg1/+ or wgSp-1/+ or Wnt2O/+ or Wnt2I/+ or Wnt2RJ/+ or pan3/+ (but not shgk03401/+) significantly partially suppresses the decreased lifespan seen in flies with expression of Hsap\HTTQ93.ex1p.Scer\UAS driven by Scer\GAL4elav.PU. Co-expression of AxnScer\UAS.cUa or Apc2Scer\UAS.cUa or sggY214F.Scer\UAS significantly partially suppresses the decreased lifespan seen in flies with expression of Hsap\HTTQ93.ex1p.Scer\UAS driven by Scer\GAL4elav.PU. Co-expression of sggScer\UAS.cBa or sggS9A.Scer\UAS leads to lethality in flies with expression of Hsap\HTTQ93.ex1p.Scer\UAS driven by Scer\GAL4elav.PU. pan3/+ or pan2/+ (but not shgk03401/+) or co-expression of AxnScer\UAS.cUa significantly partially suppresses the decreased lifespan seen in flies with expression of Hsap\HTTQ93.ex1p.Scer\UAS driven by Scer\GAL4Eaat1.PR. Co-expression of AxnScer\UAS.cUa significantly suppresses the locomotor defects and photoreceptor loss seen in flies with expression of Hsap\HTTQ93.ex1p.Scer\UAS driven by Scer\GAL4elav.PU. arm3/+ significantly suppresses photoreceptor loss seen in flies with expression of Hsap\HTTQ93.ex1p.Scer\UAS driven by Scer\GAL4elav.PU. Co-expression of AxnScer\UAS.cUa or arm3/+ significantly suppresses the locomotor defects and bang sensitivity seen in flies with expression of Hsap\HTTQ93.ex1p.Scer\UAS driven by Scer\GAL4repo.PU. Co-expression of AxnScer\UAS.cUa significantly suppresses neurophysiological defects seen in the giant fiber pathway of Scer\GAL4repo.PU>Hsap\HTTQ93.ex1p.Scer\UAS flies. Co-expression of armS10.Scer\UAS.T:Hsap\MYC significantly enhances the short lifespan seen in Scer\GAL4elav.PU>Hsap\HTTQ93.ex1p.Scer\UAS flies.
Expression of Rab11Scer\UAS.T:Avic\GFP-EGFP suppresses the reduction in average synaptic vesicle diameter seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Expression of Rab11Scer\UAS.T:Avic\GFP-EGFP suppresses the reduction in eEJP and mEJP amplitudes seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155 to levels comparable with controls. No significant difference is seen in mEJP decay kinetics, mEJP frequency, mean resting membrane potential or quantal content compared to controls. Expression of Rab11Scer\UAS.T:Avic\GFP-EGFP suppresses the third instar larval crawling defects seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4C164. The number of turns and distance travelled is comparable to controls.
Homozygous cn3 partially suppresses the rhabdomere degeneration seen in one day old flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Some rescue, albeit reduced, is also seen at seven days post-eclosion. No rescue is seen with heterozygous cn3. The increase in 3-hydroxykynurenine (3-HK)/kynurenic acid (KYNA) ratio is also significantly suppressed, with flies exhibiting ratios that are similar to those seen in cn3 mutant flies alone. Unlike when Hsap\HTTQ93.ex1p.Scer\UAS is expressed alone, treating these flies with Ro 61-8048 is unable to further rescue the rhabdomere degeneration. Feeding the flies 3-HK suppresses the protective effect of cn3 in a dose-dependent manner; at the highest dose the level of rhabdomere degeneration is similar to that seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed alone. The 3-HK/KYNA ratio is also restored. Homozygous v36f partially suppresses the rhabdomere degeneration seen in one day old flies when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Some rescue, albeit reduced, is also seen at seven days post-eclosion. Partial rescue is also seen with v36f/+. The increase in 3-hydroxykynurenine (3-HK)/kynurenic acid (KYNA) ratio is also significantly suppressed with either homozygous or heterozygous v36f, with flies exhibiting ratios that are similar to those seen in homozygous v36f mutant flies alone. Expression of cnKK101938 partially suppresses the rhabdomere degeneration seen in one day old flies when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Some rescue is seen at seven days post-eclosion. The increase in 3-hydroxykynurenine (3-HK)/kynurenic acid (KYNA) ratio is also significantly suppressed. Expression of vKK108195 partially suppresses the rhabdomere degeneration seen in one day old flies when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Some rescue is seen at seven days post-eclosion. The increase in 3-hydroxykynurenine (3-HK)/kynurenic acid (KYNA) ratio is also significantly suppressed. cd1 partially suppresses the rhabdomere degeneration seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155 at both one day and seven days post-eclosion. 3-hydroxykynurenine (3-HK) levels are unchanged but kynurenic acid (KYNA) levels are significantly increased, resulting in a significant increase in the 3-HK/KYNA ratio.
The neuronal degeneration phenotype and decreased survival of animals expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 is not suppressed in a rl10a/+ mutant background. The decreased survival phenotype of flies expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 is enhanced in a Dsor1G42/+ mutant background. The neuronal degeneration phenotype and decreased survival of animals expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 is partially suppressed in a PTP-ERXE-2776/+ background. A modest but not-significant suppression is also observed in a mtsXE-2258/+ or bsk1/+ mutant background.
Overexpression of Rab11Scer\UAS.T:Avic\GFP-EGFP almost completely suppresses the Hsap\HTTQ93.ex1p.Scer\UAS eclosion phenotype, with a greater than twofold increase in emergence. Overexpression of Rab11Scer\UAS.T:Avic\GFP-EGFP gives a highly significant 43% suppression of the rhadomere degeneration seen upon expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Overexpression of Rab11Scer\UAS.T:Avic\GFP-EGFP increases median survival of Hsap\HTTQ93.ex1p.Scer\UAS by 50% from 10 to 15 days.
When BmcpScer\UAS.cBa is co-expressed in the Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4repo background, locomotor defects are suppressed: 52% of flies reach the top of the column after a startle while <22% remain at the bottom. When BmcpScer\UAS.cBa is co-expressed in the Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4repo background, bang sensitivity is suppressed: only 23% of flies are bang sensitive. Co-expression of BmcpScer\UAS.cBa improves extends the lifespan of Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4repo flies: >78% of these flies are alive at 16 days, and life expectancy is increased by 23-25%. Co-expression of BmcpScer\UAS.cBa increases the life expectancy of Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4Eaat1.PR flies by 20%. Heterozygosity for BmcpBG02446 does not affect the short adult life span phenotype of Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4Eaat1.PR flies. Co-expression of BmcpScer\UAS.cBa does not improve the climbing ability or lifespan phenotypes of Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4elav-C155 flies. Co-expression of BmcpScer\UAS.cBa does not restore the loss of mushroom body gamma lobes seen in Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4ey-OK107 flies. When Hsap\UCP2Scer\UAS.cFa is co-expressed in the Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4repo background, the locomotor (climbing ability), bang sensitivity and reduced life span phenotypes are all suppressed. When Hsap\UCP2Scer\UAS.cFa is co-expressed in the Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4Eaat1.PR background, the reduced life span phenotype is suppressed. The presence of Sod2+t9 and CatT:mito1 does not prevent the early death of adult flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4Eaat1.PR, but does improve the survival of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. When Glut1Scer\UAS.cBa is co-expressed in the Hsap\HTTQ93.ex1p.Scer\UAS, Scer\GAL4repo background, the locomotor (climbing ability) and reduced life span phenotypes are suppressed.
The rhabdomere loss observed upon expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav.PU is partially rescued by Sirt25B-2-35 homozygosity or heterozygosity, in a dose-dependent manner.
Co-expression of PsaScer\UAS.cSa increases the lifespan of flies expressing Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS. Co-expression of PsaNIG.1009R further shortens the lifespan of flies expressing Scer\GAL4elav-C155>Hsap\HTTQ93.ex1p.Scer\UAS.
The eye degeneration phenotype caused by expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PU is suppressed by co-expression of Hsc70CbScer\UAS.cZa. The eye degeneration phenotype caused by expression of Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PU is enhanced if the flies are also heterozygous for one of Hsc70Cb00082, Hsc70CbS031820, Hsc70CbS064906, Hsc70CbS004112, Nipped-ANC116 or Nipped-ANC186.
Co-expression of two copies of P{Sym-UAS-Hsrω} substantially inhibits the age dependant degeneration of rhabdomeres seen in Hsap\HDQ93.ex1p.Scer\UAS, Scer\GAL4GMR.PF flies. Co-expression of one or two copies of P{Sym-UAS-Hsrω} restores normal phototactic behaviour to Hsap\HDQ93.ex1p.Scer\UAS, Scer\GAL4GMR.PF flies. Co-expression of a single copy of P{Sym-UAS-Hsrω} prolongs the lifespan of Scer\GAL4elav-C155, Hsap\HDQ93.ex1p.Scer\UAS flies such that it becomes comparable with controls.
Co-expression of Mmus\Bag1Scer\UAS.T:Zzzz\FLAG significantly alleviates the Scer\GAL4elav.PU, Hsap\HTTQ93.ex1p.Scer\UAS rhabdomere phenotype, resulting in higher numbers and an organization resembling that of controls.
The eye degeneration phenotype caused by expression of Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 is not enhanced in a htt98E2 background (Df(3R)98E2 homozygotes in which CG9990 function has been rescued by P{CG9990+t24.7}). The initial hyperactivity phenotype of adults expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 is not seen in a htt98E2 background. The decrease in mobility that is seen as adults expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 as they age is enhanced in a htt98E2 background. The double mutant flies also show earlier lethality than animals expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 in a wild-type background. The brains of adults expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 in a htt98E2 background show a more severe pathology at 5 days of age compared to adults expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 in a wild-type background. The mushroom bodies appear less organised (the characteristic bulged tip of the vertical α-lobes is largely unrecognizable in 95% of cases and the clear separation between the pair of medially projected β-lobes is less distinct and often appears to be merged) and they are reduced in size compared to animals expressing Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 in a wild-type background. The double mutant brains also have larger areas that are devoid of neuronal cells.
Expression of Akt1Scer\UAS.Exel strongly suppresses the pigment cell degeneration seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4GMR.PU. Expression of Akt1Scer\UAS.Exel markedly slows down the progressive photoreceptor degeneration seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Expression of Akt1Scer\UAS.Exel does not suppress the γ-lobe kenyon cell degeneration seen in the mushroom bodies when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Expression of Akt1Scer\UAS.Exel does not suppress the reduction in lifespan seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of any of Scer\GAL4elav-C155, Scer\GAL4repo.PU or Scer\GAL4Eaat1.PR. Expression of Akt1Scer\UAS.Exel does not suppress the locomotor defects seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. The locomotor defects seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4repo.PU are partially suppressed. Expression of rlSem.C.Scer\UAS does not suppress the pigment cell degeneration seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4GMR.PU. Expression of rlSem.C.Scer\UAS does not suppress the γ-lobe kenyon cell degeneration seen in the mushroom bodies when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Expression of rlSem.C.Scer\UAS does not suppress the reduction in lifespan seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of any of Scer\GAL4elav-C155, Scer\GAL4repo.PU or Scer\GAL4Eaat1.PR. Expression of Hsap\HSPA1LScer\UAS.cWa suppresses the pigment cell degeneration seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4GMR.PU. Expression of Hsap\HSPA1LScer\UAS.cWa significantly delays the progressive photoreceptor degeneration seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155. Expression of Hsap\HSPA1LScer\UAS.cWa partially suppresses the reduction in life expectancy seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of any of Scer\GAL4elav-C155, Scer\GAL4repo.PU or Scer\GAL4Eaat1.PR. Expression of Hsap\HSPA1LScer\UAS.cWa partially suppresses the locomotor defects seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of either Scer\GAL4elav-C155 or Scer\GAL4repo.PU. Expression of DnaJ-1Scer\UAS.cKa partially suppresses the reduction in life expectancy seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4Eaat1.PR. Expression of mrjScer\UAS.cFa partially suppresses the reduction in life expectancy seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4Eaat1.PR. Expression of Tpr2Scer\UAS.cKa partially suppresses the reduction in life expectancy seen when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4Eaat1.PR. Expression of Hsap\HSPA1LScer\UAS.cWa suppresses the γ-lobe kenyon cell degeneration seen in the mushroom bodies when Hsap\HTTQ93.ex1p.Scer\UAS is expressed under the control of Scer\GAL4elav-C155.
Co-expression of Hdac3dsRNA.Scer\UAS does not affect the level of survival to eclosion or neurodegeneration in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Co-expression of HDAC4dsRNA.Scer\UAS does not affect the level of survival to eclosion or neurodegeneration in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Co-expression of HDAC6dsRNA.Scer\UAS.cPa does not affect the level of survival to eclosion or neurodegeneration in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Co-expression of HdacXdsRNA.Scer\UAS.cPa does not affect the level of survival to eclosion or neurodegeneration in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. A heterozygous Rpd35-5 background markedly increases the survival rate of flies neuronally-expressing Hsap\HTTQ93.ex1p.Scer\UAS flies (from <10% to nearer 35% survival to eclosion). In addition, the level of neurodegeneration, as measured by the ratio of rhabdomeres per ommatidia, is also lowered in a Rpd35-5 heterozygous background. A heterozygous Sir217 background markedly increases the survival rate of flies neuronally-expressing Hsap\HTTQ93.ex1p.Scer\UAS flies (from <10% to nearer 35% survival to eclosion). In addition, the level of neurodegeneration, as measured by the ratio of rhabdomeres per ommatidia, is also lowered in a Sir217 heterozygous background. A reduction in the level of Sirt2, through a Sirt25B-2-35 heterozygous background, leads to greater survival of photoreceptor neurons in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155, although this background does not suppress lethality. A Rpd35-5 heterozygous background does not affect the short lifespan found in flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155. Overexpression of Sir2EP2300 does not reduce the lethality associated with expression of Hsap\HTTQ93.ex1p.Scer\UAS (when both are driven by Scer\GAL4elav-C155). Addition of resveratrol to food fed to these 'double mutant' flies rescues the neuronal degeneration phenotype found in these flies, in a dose-dependent manner.
The eye degeneration phenotype caused by expression of Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4GMR.PF is enhanced by Hsrω05241/Hsrω05241.
Neuropathology of Hsap\HDQ93.ex1p.Scer\UAS is reduced when SUMO activity is reduced, and increased, though only slightly, when flies are heterozygous for a mutation in Ubi-p63E.
Sin3A08269/+ increases the viability of flies expressing Hsap\HTTQ93.ex1p.Scer\UAS under the control of Scer\GAL4elav-C155 from 29% to 69% and reduces the extent and rate of neurodegeneration seen in these flies.
Complementation and Rescue Data
Comments
In Hsap\HDQ93.ex1p.Scer\UAS-expressing flies expressing the Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 transgene, both under the control of Scer\GAL4elav-C155, photoreceptors are significantly rescued by 48% compared to no intrabody controls. Co-expression of Hsap\HDC4sFv.Scer\UAS.T:Ivir\HA1 confers significantly improved survival on Hsap\HDQ93.ex1p.Scer\UAS flies.
Co-expression of Hsap\HDQ20.ex1p.Scer\UAS with Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4ninaE.PD results in an increase of cells with nuclear inclusions at days 5 and 6, compared to expression of just Hsap\HDQ93.ex1p.Scer\UAS alone. By day 10, almost all cell nuclei in flies expressing both Hsap\HDQ20.ex1p.Scer\UAS and Hsap\HDQ93.ex1p.Scer\UAS contain inclusions. Co-expression of Hsap\HDQ20.ex1p.Scer\UAS with Hsap\HDQ93.ex1p.Scer\UAS under the control of Scer\GAL4ninaE.PD increases the speed and severity of neuronal degeneration compared to expression of Hsap\HDQ93.ex1p.Scer\UAS alone (under the control of Scer\GAL4ninaE.PD), with an average of only 4.7 rhabdomeres per ommatidium remaining.
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Synonyms and Secondary IDs (6)
Reported As
Symbol Synonym
Hsap\HDQ93.ex1p.Scer\UAS
Hsap\HTTQ93.ex1.Scer\UAS
Hsap\HTTQ93.ex1.UAS
Hsap\HTTQ93.ex1p.Scer\UAS
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    References (65)