Flybase curator comment: Parkinson disease subtype Parkinson disease 2 is associated with gene PRKN.
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 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.
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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 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.