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General Information
Symbol
Dmel\park25
Species
D. melanogaster
Name
FlyBase ID
FBal0146938
Feature type
allele
Associated gene
Associated Insertion(s)
Carried in Construct
Also Known As
parkin25
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
Cytology
Nature of the lesion
Statement
Reference
The first three exons of the park gene have been deleted as well as half of exon 4.
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 CatUAS.cAa
is ameliorated by simaHMS00833
is exacerbated by ShmtGD8851
is ameliorated by foxoUAS.cFa
is ameliorated by Lrrke03680
is ameliorated by ThorUAS.cMa
is ameliorated by Opa1s3475
is ameliorated by Opa1f02779
is ameliorated by ParpCH1
is NOT ameliorated by Hsap\CLUHUASp.cSa
is NOT ameliorated by cluUASp.cSa
is ameliorated by PEKGD5584
is NOT ameliorated by ND-42UAS.Tag:HA
is NOT ameliorated by ND-42UAS.cBa
is NOT ameliorated by sicilyUAS.cZa
is NOT ameliorated by TER94UAS.cRa
is ameliorated by MTF-1UAS.cSa
is exacerbated by MTF-1140-1R
is NOT ameliorated by Hsap\TRAP1UAS.cBa
is ameliorated by Trap1UAS.cCa
Comments on Models/Modifiers Based on Experimental Evidence ( 3 )
 
Parkinson's disease-related phenotypes are observed in Vps35E42 park25 double heterozygotes.
Parkinson's disease-related phenotypes are observed in Vps35MH20 park25 double heterozygotes.
model of Parkinson's disease ; DOID:14330 | IC with parkΔ21
Phenotypic Data
Phenotypic Class
Phenotype Manifest In
Detailed Description
Statement
Reference
park25 leads to a significant decrease in adult locomotion capacity (in climbing assays), which is more severe in homozygosity than in heterozygosity, as compared to wild-type controls. park25 homozygous adults show a significant decrease in the number of dopaminergic PPL1 neurons at day 20 post eclosion, but not at days 5 and 10 post eclosion, as compared to heterozygous and wild-type controls. Mutant dopaminergic PPL1 neurons display mostly fragmented and progressively more spherical and swollen mitochondria, display a significant increase in the number of aged mitochondria, but not of newly synthesized mitochondria (assessed by MitoTimer), and display a significant decrease in the recruitment of autophagosomes to mitochondria at days 5 and 10, but not 20, post eclosion (assessed by fluorescence co-localization between mitoGFP and mCherry-atg8a puncta), despite of no changes in the number of autophagosomes per cell or PPL1 neuron cluster, as compared to heterozygous and wild-type controls; these mitochondrial defects are not observed in dopaminergic PPM3 neurons.
park25/park[25] homozygotes show mitochondrial defects in third instar larval body wall muscles, namely a "onion"-like phenotype and a "dumbbell" shape (i.e. the two ends of one mitochondrion stretch in the opposite directions while the outer membrane and crista junctions are intact) and in indirect flight muscles, namely vacuolated mitochondria.
park25 mutant adults show significant loss of brain dopaminergic neurons from the PPL1 cluster compared to controls.
Young park25 mutants show significantly slower memory decay (between 2min and 2hr or 3hr) in an olfactory memory aversive assay (although the flies do not display any smell perception defects, they show slightly but significantly reduced shock reactivity) compared to wild-type controls. The mutants also show relatively normal circadian locomotor activity rhythm in LD (light-dark) and most maintain discernible activity rhythmicity in DD (constant dark) albeit the rhythmicity tends to be weak; there is less of a distinction between periods of activity and inactivity and their baseline activity is elevated. Unlike in wild-type, the l-LNv neurons in park25 mutants do not show a day/night difference in spontaneous firing rate (SFR) but their resting membrane potentials, excitability and response to injected current is comparable to controls.
park25 adults present show a significant decrease in the number of dopaminergic PPL1 neurons in the adult brain and show a severe disruption in the mitochondrial network structure indirect flight muscles, accompanied by a significant reduction in ATP levels, as compared to controls.
park25 homozygote mutants show significantly increased number of mitochondria-endoplasmic reticulum contacts and loss of dopaminergic neurons of the PPl1 cluster in the adult brain compared to controls. They also display indentations on the thorax ('crushed thorax').
park25 mutant flies display a visible thoracic defect and dopaminergic PPL1 neuron loss; both phenotypes are mitigated upon feeding with a nicotinamide-supplemented diet. park25 mutants have decreased climbing ability and survival as compared to controls.
Adult park25 mutants display strongly diminished climbing ability compared to controls.
Thoracic muscles of park25/park25 mutant adults display fragmented mitochondrial cristae.
Mitochondria are mislocalized and clustered in park25/park25 or park25/Df(3L)Pc-MK germ cells in the ovary, and females have greatly reduced fertility (decreased egg-laying). park25/park25 flies have a high percentage of thoracic indentations.
Dietary C18:0 supplementation (10%) significantly increases lifespan of male park25. park25 mutant flies exhibit mitochondrial fragmentation, which is rescued by dietary supplementation with C18:0.
These heterozygote adults are short lived compared to controls.
Mitochondria from park25 indirect flight muscles show defective morphology - disorganized cristae and enlarged size. Dopaminergic neurodegeneration or dopamine depletion is not seen in park25 mutants.
3-5 day old park1/park25 mutant flies show indirect flight muscle degeneration. One or several of the six muscles has highly degenerated, highly irregular myofibrils with abnormal sarcomere structure in 65% of the animals as compared to controls. The indirect flight muscles of park1/park25 mutants display a heterogeneous population of mitochondria with the majority having significantly enlarged sizes and mild or severe disruption of their cristae structure, when compared to control mitochondria. Severely enlarged mitochondria are also seen in dopaminergic neurons. park1/park25 mutants show reduced ATP content in the thorax to approximately 40% of controls. Complex 1 activity is not significantly different from controls.
The kinetics of the clearance of the paternal mitochondrial derivatives is normal in embryos derived from park25/Df(3L)Pc-MK females. The kinetics of the clearance of the paternal mitochondrial derivatives is normal in embryos derived from park25/parkZ472 males whose fertility has been rescued until a late spermatid stage by expression of parkT:Zzzz\TEV.CS followed by inactivation of the rescuing protein using cleavage by Zzzz\NIadj.PP.
Mutant adults have an indentation on the dorsal thorax.
Nicotine exposure increases median lifespan in park25 heterozygotes, as opposed to decreasing life expectancy, as found in control flies. Nicotine exposure prevents park25 heterozygote climbing and olfactory deficits and ameliorates flying deficits. Unlike park25 homozygotes, park25 heterozygotes experience no dopaminergic neuron loss (as determined by ple expression) compared to wild-type flies. park25 homo- and hetero-zygotes exhibit a decreased median lifespan compared to control flies (26 days compared to 64 days). Heterozygous park25 mutants have a delayed-onset, progressively decreasing climbing ability, compared to wild-type. Heterozygous park25 mutants have a delayed-onset, progressively decreasing flying ability, compared to wild-type. This phenotype is ameliorated at all stages by addition of <12υg/ml nicotine.
park25 mutants are short lived and have impaired climbing ability at days 3 posrt eclosion, compared to controls. Mutant flies have thoracic indentations.
Most park25 adults have indentations in the dorsal thorax. Mutant adults show reduced climbing ability compared to controls.
Homozygous flies often have an abnormal wing posture. Climbing index is reduced compared to wild type. Indirect flight muscles show vacuolisation.
Mutant adults often show an indented thorax phenotype.
The mean speed of park25/parkZ3678 or park25/park25 larvae is significantly reduced compared to wild type. The frequency of peristaltic contractions and motoneuron bursts in park25/park25 larvae are significantly reduced compared to wild type. The muscle membrane potential of park25/parkZ3678 or park25/park25 larvae is significantly reduced (more positive) compared to wild type. Excitatory junction potentials (type Is) and miniature excitatory junction potentials are smaller in park25/parkZ3678 larvae than wild type. park25/park25 larvae consume significantly less oxygen, are significantly more sensitive to metabolic poisons (cyanide, iodoacetate) and have significantly reduced ATP levels compared to wild type. Lactate concentration is significantly increased in park25/park25 or park25/parkZ3678 larvae compared to wild type. The number of synaptic boutons on muscle 6/7 is significantly increased in park25/park25 third instar larvae compared to wild type.
One copy of park25 enhances the wing phenotypes seen when parkVDRC.cUa is expressed under the control of Scer\GAL4tub.PU.
park25 mutant females lack the proper spatiotemporal development in the germarium and thus have stunted ovaries with few mature oocytes, which fail to get fertilised. park25 mutant flies exhibit abnormal thoracic muscle structure, with large vacuoles, a reduced muscle content with a mostly irregular arrangement and enlarged mitochondria with disintegrated cristae. park25 homozygotes display reduced basal levels of zinc, copper and iron in comparison to control flies. Supplementation of fly food with these metals restores basal levels to almost control levels.
park25/park25 mutants display abnormal wing posture, thoracic muscle defects with presence of abnormal vacuoles, and muscle apoptosis as seen with TUNEL staining.
The addition of 4mM ZnCl[[2]] increases the longevity of park25 mutant flies. The maximum lifespan of 11 days on normal food is increased to 23 days, with the median lifespan extended from 6 days to 22 days. Wild-type flies display the opposite phenotype. The strongest positive effect of zinc on park25 mutant flies is found when they are both raised and maintained on 4mM Zn-supplemented food. park25 mutant flies absorb less Zn than controls, and indeed, are less sensitive to the negative effects of Zn in food. Zinc supplementation increases the eclosion frequency of park25 mutants, from 2.5% to 19%. In contrast, heterozygous flies do not exhibit such a change.
park25 homozygotes show significantly shortened lifespan after treatment with 10mM paraquat, 200υM rotenone and 25mM MMP[+]. In contrast, heterozygotes and control flies do not show increased sensitivity or reduced lifespans upon exposure to paraquat or rotenone. Unexpectedly, park25 heterozygotes treated with MMP[+] exhibit similar lifespan to equally treated controls. There is no difference in the number of ple-positive (i.e. dopamine-synthesising) neurons in park25 flies compared to wild-type. Addition of both 0.1mM bathocuproine disulfonate and 0.3mM bathophenanthroline to the diet of park25 homozygous flies significantly prolongs their median lifespan, from 5 to 19 days. In contrast, metal chelation does not increase the lifespan of park25 heterozygotes. There is no difference in the amount of food ingested by park25 homo- and heterozygotes fed with metal chelator-supplemented food, compared to normal food. Exposure to increased levels of iron slightly but significantly reduces the lifespan of park25 homozygous flies, without exerting an effect on park25 heterozygous flies. In contrast, increasing the copper concentration in the food fails to shorten the lifespan of either genotype of flies. Addition of either 15mM N-acetylcysteine or 100mM ascorbic acid significantly increases the median lifespan of park25 homozygous flies from 5 days to 14 and 10 days, respectively. However, higher concentrations of ascorbic acid are ineffective and even shorten lifespan. park25 flies exhibit wild-type eyes. The recovery of park25 homozygous flies from a 7 minute exposure to 0.5% oxygen in a hypoxia chamber is significantly delayed when compared to park25 heterozygotes. In addition, a heat shock for 30 or 60 minutes at 38[o]C results in a dramatic increase in mortality in park25 homozygotes, with only 15% and 7% of flies surviving, while at least 95% of park25 heterozygotes survive the same treatments.
park25/park25 flies have significant defects in climbing and flight ability, as well as muscle degeneration and mitochondrial disruption, compared to heterozygotes; 30 day old mutants show significant loss of dopaminergic PPL1 neurons. park25/park25 flies have significant indentations in the thorax (indications of flight muscle degeneration).
Mutant leaf blade spermatids contain only one mitochondrial derivative compared with the two seen in wild type. Indirect flight muscles of mutant flies show severe defects in mitochondrial morphology, including swollen mitochondria with broken cristae. Vacuolisation, indicative of degeneration, is seen in the indirect flight muscles.
park25/park25 mutant adults display thoracic indentations, impaired flight ability, climbing defects, and mitochondrial morphological defects. park25/parkZ472 mutant adults display thoracic indentations and impaired flight ability.
Spermatid elongation in park25 mutants follows the usual pattern observed in wild-type testis. The overall length of the fully elongated spermatid cysts varies from 1.65 to 2.03mm in park25 mutants and 1.85 to 2.13mm in control flies. In testes from park25 mutants, not all the spermatid nuclei are aligned in register; some of them are mispositioned along the cyst length. The investment cones (ICs) are located in position distant from the nuclear region, indicating that they have translted along the spermatid bundles. However, they are not aligned as in wild-tpye, but are scattered along the sperm tail, suggesting that they do not move in synchrony. The individual ICs are cone-shaped as in wild-type. Normally, their apex points toward the apical region of the cyst, where the nuclei are aligned, and their basis is toward the tips of the tails. Among the fully elongated spermatid cysts examined, 19% of them display 9-10% of misoriented ICs. 'Waste bags' in park25 testes are not distinct as in wild-type, suggesting that the process of individualisation is not properly executed in these mutants. This is confirmed by the finding of irregularly coiled distal ends of the spermatid bundles. Mitochondria aggregate in a loose cluster around the nuclei in both wild-type and mutant spermatids at the end of meiosis. No significant differences in nebenkern morphology are observed in young wild-type or mutant spermatids. During earlier stages of elongation, the round wild-type spermatids still show a spherical nuclues, but the nebenkern starts to elongate and a distinct paried structure is readily observed. park25 mutant spermatids at the same stage show an elongated nebenkern that does not resolve into two parts. While mitochondria form concentric ring-like structures in wild-type nebenkern, their arrangement is more iiregular in mutant spermatocytes. The park25 nebenkern is, indeed, formed by a large portion of rather ring-like concentric mitochondria, and a small portion of loose peripheral mitochondria, that do not seem to integrate into the tightly packed main cluster. The concentric mitochondria, moreover, appear more electron-dense in mutant than in wild-type spermatids. Cross-sections through park25 spermatocytes reveal only one large mitochondrion associated with the growing flagellum during axoneme elongation, while in wild-type there are two mitochondrial derivatives. Sections through park25 mutant spermatid bundles that appear slightly elongated (as judged by the hooked peripheral arms growing by the B-subfiber), show both ring-like and spherical mitochondria. This suggests that park25 mitochondria undergo compaction as the spermatid elongates. At a comparable developmental stage, the pre-individualization park25 spermatids maintain some cytoplasmic ground substance and are connected by intercellular bridges. The spermatids usually contain a single irregularly shaped and sized mitochondrion surrounded by disorganised sheaths of microtubules. These microtubules are scattered in the spermatid cytoplasm and occasionally localised near the axoneme. The organisation of the axonemal microtubules is normal, whereas the orientation of the mitochondrial derivatives varies within the same cyst. Mitochondrial condensation is highly defective: some mitochondria are filled with dense material in the region adjacent to the axoneme, whereas others do not show appreciable signs of condensation or the condensation is barely detectable. Closely paired axonemes are also found in these cysts, whereas wild-type cysts contain evenly spaced axonemes. Towards the distal region of post-elongating wild-type spermatid bundles, the size of the mitochondrial derivatives decreases. In the same stage in park25 mutant speramtids, one mitochondrion alone, abnormally shaped and of varying size, is usually found. Mitochondrial condensation is also defective. Mitochondria are found filled with large dark masses, along with pale mitochondria with evident cristae remnants in the same cyst. Sections of mutant spermatids that appear quite mature on the basis of axonemal decoration reveal that only a few spermatids are apparently cellularized. Most of the spermatids are immersed in a large amount of cytoplasmic ground substance, and their mitochondrial derivatives appear irregularly condensed and abnormally sized.
1-day old park25 mutant adults, relative to age-matched controls exhibit a significant reduction in the number of dopaminergic (DA) neurons in one of the clusters, the protocerebral posterior lateral (PPL). At 20-days old, the ple-positive protocerebral posterior lateral 1 (PPL1) cluster exhibits a further decrease in number. No significant difference is observed in any other dopaminergic (DA) neuron cluster in 20-day old park25 adults. In contrast, the number of ple-positive neurons in the PPL cluster during the late pupal stage, in which the adult CNS is already fully formed, is indistinguishable between park25 mutants and wild-type controls. park25 mutants exhibit a strong climbing defect, in which geotactic climbing behaviour is restricted in the larvae. park25 mutants do not exhibit any gross anatomical defects or differences in levels of apoptosis in the cortical or neuropil regions of the adult brain. Furthermore, no dramatic differences in dopaminergic (DA) neurons are observed between park25 and wild-type neurons. No significant differences in the number of serotonergic neurons are observed in 20-day old park25 mutants compared to wild-type controls.
park25/Df(3L)Pc-MK animals eclose a day later than wild-type and have an average lifespan of 27 days (as opposed to 39 days for wild-type). Mutant animals exhibit a downturned wing phenotype. This phenotype becomes moire penetrant with age; about 40% of newly eclosed flies exhibit abnormal wing posture, whereas by 10 days of age more than 70% of animals have this phenotype. Mutant adult indirect flight muscles show an irregular and dispersed myofibrillar arrangement with diffuse Z-lines and M-bands. Mitochondria are grossly swollen and malformed showing disintegration of cristae. The mitochondrial pathology is progressive and preceeds myofibril degeneration. Homozygous adults exhibit apoptotic cell death of the flight muscle.
External Data
Interactions
Show genetic interaction network for Enhancers & Suppressors
Phenotypic Class
Enhanced by
NOT Enhanced by
Statement
Reference
Suppressed by
Statement
Reference
park25 has short lived phenotype, suppressible | partially by Parp[+]/ParpCH1
park25 has visible phenotype, suppressible | partially by Parp[+]/ParpCH1
park25 has neuroanatomy defective | adult stage phenotype, suppressible by Parp[+]/ParpCH1
parkΔ21/park25 has flight defective phenotype, suppressible | partially by mask[+]/mask10.22
park25 has short lived phenotype, suppressible by MTF-1αTub84B.PS
park25 has short lived | chemical conditional phenotype, suppressible by Hsap\SOD1UAS.cWa/Scer\GAL4twi.PG
park25 has long lived | recessive | chemical conditional phenotype, suppressible by Hsap\SOD1UAS.cWa/Scer\GAL4twi.PG
parkZ472/park25 has flight defective phenotype, suppressible | partially by Opa1[+]/Opa1s3475
park25 has flight defective phenotype, suppressible | partially by Opa1[+]/Opa1f02779
parkZ472/park25 has flight defective phenotype, suppressible | partially by Opa1[+]/Opa1f02779
NOT suppressed by
Statement
Reference
park25 has visible phenotype, non-suppressible by cluUASp.cSa/Scer\GAL4Mhc.PW
park25 has male sterile phenotype, non-suppressible by MTF-1αTub84B.PS
park25 has visible phenotype, non-suppressible by DJ-1αUAS.cUa/Scer\GAL4how-24B
park25 has locomotor behavior defective phenotype, non-suppressible by Pink1B9
park25 has flight defective phenotype, non-suppressible by Opa1[+]/Opa1s3475
Enhancer of
NOT Enhancer of
Statement
Reference
Suppressor of
NOT Suppressor of
Other
Phenotype Manifest In
Enhanced by
NOT Enhanced by
Statement
Reference
parkΔ21/park25 has adult external thorax phenotype, non-enhanceable by Atg18aKG03090/Atg18a[+]
park25 has adult thorax | dorsal phenotype, non-enhanceable by Pink15
Suppressed by
Statement
Reference
park25 has adult thorax phenotype, suppressible | partially by Parp[+]/ParpCH1
park25 has dopaminergic PPL1 neuron phenotype, suppressible by Parp[+]/ParpCH1
parkΔ21/park25 has adult external thorax phenotype, suppressible | partially by mask[+]/mask10.22
park25 has ovary phenotype, suppressible by MTF-1αTub84B.PS
park25 has oocyte phenotype, suppressible by MTF-1αTub84B.PS
park25 has adult thorax phenotype, suppressible | partially by Opa1[+]/Opa1s3475
park25 has mitochondrion phenotype, suppressible by Opa1[+]/Opa1s3475
parkZ472/park25 has adult thorax phenotype, suppressible | partially by Opa1[+]/Opa1s3475
park25 has adult thorax phenotype, suppressible | partially by Opa1[+]/Opa1f02779
parkZ472/park25 has adult thorax phenotype, suppressible | partially by Opa1[+]/Opa1f02779
park25 has adult thorax phenotype, suppressible | partially by +/Df(1)Exel6239
NOT suppressed by
Statement
Reference
park25 has wing phenotype, non-suppressible by Hsap\TRAP1UAS.cBa/Scer\GAL4da.G32
park25 has wing phenotype, non-suppressible by DJ-1αUAS.cUa/Scer\GAL4how-24B
Enhancer of
Statement
Reference
NOT Enhancer of
Statement
Reference
park25 is a non-enhancer of adult thorax | dorsal phenotype of Pink15
Suppressor of
NOT Suppressor of
Statement
Reference
park25 is a non-suppressor of eye | chemical conditional phenotype of Ctr1BGMR.PS
Other
Additional Comments
Genetic Interactions
Statement
Reference
The increased lethality of park25 homozygous adults is worsened further by expression of crcKK111018 under the control of Scer\GAL4da.PU and the penetrance of the mutant crushed-thorax phenotype is also significantly increased. A strong increase in lethality of park25 mutants is also seen upon Scer\GAL4da.PU-driven expression of either Shmt2GD8851 or NmdmcKK102478 (hardly any adults can be recovered). Expression of either Shmt2Scer\UAS.T:Ivir\HA1 or NmdmcScer\UAS.T:Ivir\HA1 (but not Gcn2KK103566) driven by Scer\GAL4elav.PU significantly rescues the loss of dopaminergic ppl1 cluster neurons characteristic for park25 mutant adults.
Individuals both mutant for park25 and expressing Stoml2GD16706 under the control of Scer\GAL4ple.PU show a more severe decrease in the number of PPL1 neurons in the adult brain than either individual mutant condition. The expression of Stoml2UAS.cZa under the control of Scer\GAL4ple.PU partially restores the decreased number of dopaminergic PPL1 neurons observed in park25 mutants.
The increased number of mitochondria-endoplasmic reticulum contacts observed in the brain of adult park25 homozygotes is strongly suppressed by expression of MarfKK105681 RNAi under the control of Scer\GAL4elav.PU in the mutant background. Expression of MarfKK105681 under the control of Scer\GAL4da.PU strongly suppresses the 'crushed thorax' phenotype characteristic for park25 homozygote adults. Expression of PEKGD5584 under the control of Scer\GAL4elav.PU significantly rescues the loss of dopaminergic neurons characteristic for adult park25 homozygote mutants.
park25, ParpCH1/+ double mutants display a reduced thoracic defect, and partially rescued climbing performance and survival, as compared to park25 mutants. The dopaminergic neuron phenotype of park25 is fully rescued in park25, ParpCH1/+ double mutants.
The reduced climbing ability phenotype observed in park25 mutant adults or in flies expressing simaHMS00833 under the control of Scer\GAL4da.PU is (partially) mutually suppressible.
Vps35MH20 park25 double heterozygotes show an age-dependent reduction in climbing ability. No phenotypes are observed in either heterozygote alone. Vps35MH20 park25 double heterozygotes show increased sensitivity to the oxidative stressor paraquat compared with either heterozygote alone, similar to that seen in park25 homozygotes. In contrast to either heterozygote alone, progressive degeneration of the dopaminergic neurons in the PPPL cluster is also seen in Vps35MH20 park25 double heterozygotes. Vps35E42 park25 double heterozygotes show an age-dependent reduction in climbing ability. No phenotypes are observed in either heterozygote alone. Vps35E42 park25 double heterozygotes show increased sensitivity to the oxidative stressor paraquat compared with either heterozygote alone, similar to that seen in park25 homozygotes. Expression of Vps35Scer\UAS.cMa under the control of Scer\GAL4da.PU suppresses the climbing defects and increased sensitivity to paraquat seen in park25 mutants. The flight defect is not suppressed. Expression of Vps35Scer\UAS.D650N under the control of Scer\GAL4da.PU suppresses the climbing defects and increased sensitivity to paraquat seen in park25 mutants. Expression of Vps35Scer\UAS.R550W under the control of Scer\GAL4da.PU suppresses the climbing defects and increased sensitivity to paraquat seen in park25 mutants. Expression of Vps35Scer\UAS.L800M under the control of Scer\GAL4da.PU suppresses the climbing defects and increased sensitivity to paraquat seen in park25 mutants.
Thoracic indentations seen in park25/park25 flies are not suppressed by expression of cluScer\UAS.P\T.cSa driven by Scer\GAL4Mhc.PW.
Expression of maskHMS01045 RNAi suppresses the short lived phenotype of park25/parkΔ21 transheterozygote adults.
Scer\GAL4Act5C.PI-mediated expression of USP30NIG.3016R largely restores the park25 mitochondrial morphology defects.
Expression of RetMEN2B.Scer\UAS under the control of Scer\GAL4Mef2.PR does not suppress the muscle morphology phenotype seen in the indirect flight muscles of park1/park25 mutants. The frequency of flies with "actin blobs" is decreased markedly compared to RetMEN2B.Scer\UAS expressing controls. The structural impairments seen in park1/park25 mutant mitochondria are not suppressed. The reduction in thoracic ATP levels is not rescued. Expression of RetMEN2B.Scer\UAS under the control of Scer\GAL4Mhc.PK (limited to the pharate adult stages onwards using Scer\GAL80ts.αTub84B) does not suppress the muscle morphology phenotype seen in the indirect flight muscles of park1/park25 mutants. Expression of RetMEN2B.Scer\UAS under the control of Scer\GAL4ple.PF does not suppress the mitochondrial morphology defects seen in park1/park25 mutant dopaminergic neurons.
Ubiquitous expression of ND-42Scer\UAS.cBa under the control of Scer\GAL4da.PU does not rescue the climbing and flight defects seen in park25 mutant flies. The flight muscle and mitochondrial integrity defects and male sterility are also not rescued. Expression of ND-42Scer\UAS.cBa under the control of Scer\GAL4da.PU does not rescue the reduction in ATP levels seen in park25 mutant flies. Complex I levels remain unchanged from wild type. Ubiquitous expression of ND-42Scer\UAS.T:Ivir\HA1 under the control of Scer\GAL4da.PU does not rescue the climbing and flight defects seen in park25 mutant flies. Ubiquitous expression of sicilyScer\UAS.cZa under the control of Scer\GAL4da.PU does not rescue the climbing and flight defects seen in park25 mutant flies. The flight muscle and mitochondrial integrity defects are also not rescued. Expression of sicilyScer\UAS.cZa under the control of Scer\GAL4da.PU does not rescue the reduction in complex I and ATP levels seen in park25 mutant flies.
The degree of thoracic indentation seen in park25 Pink15 double mutants is the same as that seen in either single mutant. The mitochondrial morphology in the indirect flight muscles of the double mutants is similar to that seen in the single mutants. The degree of thoracic indentation seen in park25 Mul1A6 is much more severe than that seen in park25 single mutants. The thoracic indentation phenotype of park25 Mul1A6 double mutants is almost completely suppressed by expression of MarfmiRNA.cUa.Scer\UAS under the control of Scer\GAL4unspecified. The indirect flight muscles of park25 Mul1A6 mutants have highly elongated and interconnected mitochondria. This phenotype can be suppressed by expression of MarfmiRNA.cUa.Scer\UAS under the control of Scer\GAL4unspecified.
Expression of Trap1Scer\UAS.cCa under the control of Scer\GAL4Act5C.PU partially suppresses the thoracic indentation phenotype which is seen in park25 flies. Expression of Trap1Scer\UAS.cCa under the control of Scer\GAL4Act5C.PU does not rescue the impaired climbing ability of 3 day old park25 flies. Expression of Trap1Scer\UAS.cCa under the control of Scer\GAL4Act5C.PU in park25 flies improves their lifespan and resistance to paraquat.
Expression of TER94Scer\UAS.cRa under the control of Scer\GAL4EDTP-DJ694 enhances the thorax indentation phenotype seen in park25 adults, but has no significant effect on the climbing defect seen in these animals.
Expression of ref(2)PScer\UAS.T:Ivir\HA1 under the control of Scer\GAL4Act.PU does not suppress the indented thorax phenotype seen in park25 flies.
Expression of Sod2Scer\UAS.cMa or CatScer\UAS.cAa under the control of Scer\GAL4Act5C.PU suppresses the synaptic overgrowth, but not the locomotion defects of park25/park25 larvae. Expression of Sod2Scer\UAS.cMa or CatScer\UAS.cAa under the control of Scer\GAL4Act5C.PU does not rescue the muscle resting membrane potential of park25/parkZ3678 larvae.
park25/MTF-1140-1R double mutants are synthetic lethal at the pupal stage. Raising these flies on 15Mm N-acetylcysteine, a precursor to glutathione overcomes the synthetic lethality seen in these double mutants. the presence of ascorbate, zinc, or metal chelators of copper and iron does not rescue synthetic lethality. The presence of MTF-1αTub84B.PS rescues the synthetic lethality found in park25/MTF-1140-1R double mutants. Elevated expression of MTF-1, through expression of MTF-1αTub84B.PS prolongs the life span of park25 mutants significantly, from a median of 7 days for the mutants alone to 21 days. The maximal life span was extended from 12 to 41 days by the MTF-1αTub84B.PS transgene. Elevated MTF-1 expression not only prolongs the life span of park25 mutant flies but also enhances survival during development. Elevated expression of MTF-1, through expression of MTF-1Scer\UAS.cSa under the control of Scer\GAL4Act5C.PI prolongs the life span of park25 mutants significantly, with 10% of the mutant animals still alive at day 34. Elevated MTF-1 expression not only prolongs the life span of park25 mutant flies but also enhances survival during development. Female fecundity is completely rescued by MTF-1. When crossed with wild-type males, park25 mutant females with MTF-1αTub84B.PS reproduce the same number of progeny as a cross of wild-type males and females. Dissected ovaries from these females show a normalised structure with follicles formed in the germarium and mature stages in the posterior regions of the ovariole, with several oocytes ready for fertilisation. In contrast, the sterility phenotype of park25 mutant males, which is due to defective spermatogenesis at the individualization step, is not rescued, indicated a role for park in male fertility. Strong MTF-1αTub84B.PS expression dramatically improves the climbing ability of park25 mutant flies. Furthermore, these flies generally move around very fast, and respond by running away when physically perturbed, jumping and occasionally displaying short flight episodes. Expression of MTF-1Scer\UAS.cSa under the control of Scer\GAL4Act5C.PI rescues the defect in thoracic muscle fiber structure seen in park25 mutants. Muscle structure is more regular, with fewer prominent vacuoles and the mitochondria have more densely packed cristae with considerably fewer signs of disintegration in comparison to park25 mutants. MTF-1αTub84B.PS expression restores the basal levels of zinc, copper and iron found in park25 homozygotes.
Expression of DJ-1αScer\UAS.cUa under the control of Scer\GAL4how-24B is unable to rescue the thoracic muscle defects and apoptosis phenotype of park25/park25 mutants.
Overexpression of Ctr1BGMR.PS in park25 homozygotes results in a rough eye phenotype. This phenotype can be alleviated by copper scarcity and exacerbated by increased copper levels. The rough eye phenotype is not seen upon expression of Ctr1BGMR.PS in a park25 heterozygous background. Overexpression of Ctr1BGMR.PS in park25 homozygotes raised on food supplemented with 20υM or 50υM silver nitrate fails to cause a rough eye phenotype, indicating that silver effectively competes with and inhibits copper import.
The climbing ability of park25 Pink1B9 double mutants is not significantly different from the climbing ability of either single mutant. HtrA2Δ1 park25 double mutants have dramatically enhanced defects in climbing ability compared to park25 single mutants.
Thor2/Thor2; park25/park25 double mutants are almost completely lethal (unlike either viable single mutant or viable single mutants with the other allele heterozygotic), with rare escapers dying soon after eclosion; expression of ThorScer\UAS.cMa driven by Scer\GAL4da.PU suppresses this lethality in double mutants. Expression of ThorScer\UAS.cMa or foxoScer\UAS.cFa driven by Scer\GAL4how-24B significantly partially suppresses flight and climbing defects as well as muscle degeneration and mitochondrial disruption in park25/park25 flies. Expression of ThorScer\UAS.cMa or foxoScer\UAS.cFa driven by Scer\GAL4ple.PF significantly suppresses loss of dopaminergic PPL1 neurons in 30 day old park25/park25 flies. Lrrke03680 suppresses flight and climbing defects as well as dopaminergic PPL1 neuron loss in park25/park25 flies.
Expression of either MarfmiRNA.CDS.Scer\UAS or MarfmiRNA.UTR.Scer\UAS under the control of Scer\GAL4how-24B suppresses the defects in mitochondrial morphology that are seen in the indirect flight muscles of park25 mutants. The indirect flight muscle degeneration phenotype is also suppressed. Expression of Drp1Scer\UAS.cDa under the control of Scer\GAL4how-24B suppresses the defects in mitochondrial morphology that are seen in the indirect flight muscles of park25 mutants. The indirect flight muscle degeneration phenotype is also suppressed.
Expression of Pink1Scer\UAS.T:Ivir\HA1 under the control of Scer\GAL4unspecified does not rescue the flight defects of park25/park25 mutants. Drp1T26/+ or Drp1KG03815/+ in combination with park25/park25 mutants result in lethality. Viability of flies Drp1T26/+ or Drp1KG03815/+ is unaffected in a park25/+ background. Opa1s3475/+ fully suppresses the mitochondrial morphology phenotype, and partially suppresses the thoracic indentation and impaired climbing phenotypes (but not impaired flight) of park25/park25 mutants, and partially suppresses the thoracic indentation and impaired flight phenotypes of park25/parkZ472 mutants. Opa1f02779/+ partially suppresses the thoracic indentation and impaired flight phenotypes of park25/park25 or park25/parkZ472 mutants. Df(1)Exel6239/+ almost fully suppresses the thoracic indentation phenotype, and partially suppresses the flight and climbing phenotypes of park25/park25 mutants. The rough eye phenotype of flies expressing Pink1Scer\UAS.T:Ivir\HA1 under the control of Scer\GAL4GMR.PF or Scer\GAL4ey.PH is suppressed in a park25/park25 background. The lethality phenotype of flies expressing Pink1Scer\UAS.T:Ivir\HA1 under the control of Scer\GAL4Mef2.PR is partially rescued in a park25/park25 background.
park25 partially suppresses the rough eye and ommatidial organisation phenotypes seen when Pink1Scer\UAS.T:Ivir\HA1 is expressed under the control of Scer\GAL4GMR.PF. Addition of HtrA2Δ1 suppresses the phenotype completely. park25 partially suppresses the rough eye phenotype seen when rho-7Scer\UAS.cWa is expressed under the control of Scer\GAL4GMR.PF. Expression of HtrA2Scer\UAS.cPa enhances the disorganised eye phenotype seen when Pink1Scer\UAS.T:Ivir\HA1 is expressed under the control of Scer\GAL4GMR.PF, resulting in a significant reduction in eye size. This phenotype is not suppressed in a park25 mutant background. Expression of HtrA2Scer\UAS.cPa enhances the rough eye phenotype seen when rho-7Scer\UAS.cWa is expressed under the control of Scer\GAL4GMR.PF, resulting in severe loss of eye tissue. This phenotype is not suppressed by park25.
The homozygous park25 mutant climbing defect is enhanced when heterozygous with GstS1EP2223, GstS1k09303, GstS1k08805, and GstS104227 mutants. GstS1 mutants have no effect on climbing ability in heterozygous park25 mutants. Overexpression of GstS1Scer\UAS.P\T.cWa, only in the dopaminergic (DA) neurons, through the regulation of Scer\GAL4ple.PF results in significant attenuation of the loss of DA neurons in 20-day old park25 mutants. park25 mutants bearing the GstS1M26 mutation in trans with Df(2R)ED1 (in which GstS1 is deleted) are recovered at low frequency and display a dramatically shortened lifespan. Analysis of DA neuron integrity in 1-day old park25 mutants bearing this combination of GstS1 alleles reveals significantly enhanced DA neuron loss relative to park25 mutants. Loss of GstS1 function alone has no affect on DA neuron viability in 1-day old adults.
Xenogenetic Interactions
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Reference
The expression of Hsap\STOML2UAS.cZa partially restores the decreased number of dopaminergic PPL1 neurons (Scer\GAL4ple.PU-driven expression) observed in park25 mutants.
Expression of Hsap\BNIP3LScer\UAS.cGa under the control of Scer\GAL4hs.PU fails to rescue the fragmented mitochondrial morphology of park25/park25 mutants.
Expression of Hsap\VPS35Scer\UAS.cMa under the control of Scer\GAL4da.PU suppresses the climbing defects and increased sensitivity to paraquat seen in park25 mutants. The flight defect is not suppressed. Expression of Hsap\VPS35D620N.Scer\UAS under the control of Scer\GAL4da.PU suppresses the climbing defects and increased sensitivity to paraquat seen in park25 mutants. Expression of Hsap\VPS35R524W.Scer\UAS under the control of Scer\GAL4da.PU suppresses the climbing defects and increased sensitivity to paraquat seen in park25 mutants. Expression of Hsap\VPS35L774M.Scer\UAS under the control of Scer\GAL4da.PU suppresses the climbing defects and increased sensitivity to paraquat seen in park25 mutants.
Thoracic indentations seen in park25/park25 flies are not suppressed by expression of Hsap\CLUHScer\UAS.P\T.cSa driven by Scer\GAL4Mhc.PW.
Expression of Scer\GAL4da.G32>Hsap\FBXO7Scer\UAS.cBb significantly suppresses the park25 phenotypes, including locomotor defects, dopaminergic neuron loss, muscle degeneration, and mitochondrial disruption.
Expression of Hsap\TRAP1Scer\UAS.cBa under the control of Scer\GAL4da.G32 does not significantly rescue the abnormal wing posture, reduced climbing ability or indirect flight muscle defects of homozygous park25 flies.
The life span of park25 mutants is increased from a median of 7 days to 19 days, upon expression of Hsap\MTF1Scer\UAS.P\T.cBa under the control of Scer\GAL4Act5C.PI.
park25 mutant flies expressing Hsap\SOD1Scer\UAS.cWa under the control of Scer\GAL4twi.PG do not show a difference in survival compared to park25 flies, up to 4 days of age. However, at 11 days of age only 10% of the park25 flies remain, compared to 80% of the park25 flies expressing Hsap\SOD1Scer\UAS.cWa under the control of Scer\GAL4twi.PG. None of the park25 flies survive to 17 days of age, at which time point approximately 80% of Hsap\SOD1Scer\UAS.cWa-expressing flies are still alive.
Expression of Hsap\PARK2Scer\UAS.cYa under the control of Scer\GAL4Mef2.PR fully rescues the thoracic indentation and flight phenotypes of park25/park25 mutants.
Complementation and Rescue Data
Comments
Expression of parkScer\UAS.cGa under the control of the Scer\GAL4how-24B driver rescues the defective mitochondria observed in body wall muscles of park25/parkΔ21 third instar larvae.
Expression of parkScer\UAS.cGa with a global (Scer\GAL4Act5C.PU) or neuronal (Scer\GAL4elav.PLu), but not muscle (Scer\GAL4G14), driver rescues locomotion in park25/parkZ3678 larvae; global and neuronal (but not muscle) expression partially rescues locomotion in park25/park25 larvae; neuronal but not muscle driver rescues contraction frequency in park25/park25 larvae; muscle expression rescues muscle resting membrane potential but not synaptic potential in park25/parkZ3678 larvae; neuronal expression partially rescues synaptic potential but not muscle resting membrane potential in park25/parkZ3678 larvae; global, neuronal and muscle drivers rescue synaptic overgrowth in park25/park25 larvae.
Expression of parkScer\UAS.cGa in the PPL neurons, under the regulation of Scer\GAL4ple.PF significantly attenuates dopaminergic (DA) neuron loss in the PPL cluster in park25 mutants.
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