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General Information
Symbol
Hsap\LRRK2G2019S.UAS.Tag:FLAG
Species
H. sapiens
Name
FlyBase ID
FBal0249097
Feature type
allele
Associated gene
Associated Insertion(s)
Carried in Construct
Also Known As
UAS-LRRK2-G2019S, UAS-G2019S-LRRK2, UAS-G2019S
Key Links
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 regulatory sequences drive expression of a G2019S mutant form of Hsap\LRRK2 with an N-terminal Tag:FLAG-tag.

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
Comments on Models/Modifiers Based on Experimental Evidence ( 1 )
 

Expression of the G2019S form of Hsap\LRRK2 (the most common Parkinson's disease-related mutation in humans) in dopaminergic neurons in flies results in functional and anatomical loss of visual response, providing a tractable model of visual problems which are a symptom of Parkinson's disease. The G2019S protein appears to be acting as a gain-of-function mutation in the flies.

Disease-implicated variant(s)
 
This allele represents a human variant implicated in disease.
LRRK2:p.Gly2019Ser
Variants Synonym(s)
Associated human disease model(s)
External database links
Comments concerning this variant
Phenotypic Data
Phenotypic Class
Phenotype Manifest In
Detailed Description
Statement
Reference

The expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PF leads to a significant decrease in proboscis extension reflex (in starved flies exposed to a moderate sugar stimulus), as compared to controls; these flies exhibit a significantly slower proboscis extension speed compared to controls.

Flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4Ddc.PU exhibit early death, dopaminergic neuron degeneration, and locomotor impairment as measured in climbing assays.

Expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PF results in significantly reduced contrast response function measured by steady-state visual evoked potentials method in 7-day-old adult flies.

Flies of young age expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG in dopaminergic neurons under the control of Scer\GAL4VGlut-OK371 show significant differences in visual responses compared with wild-type. Unlike in wild-type, the contrast sensitivity of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG-expressing flies increases dramatically. Expression of Scer\GAL4VGlut-OK371>Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG has an effect on both the photoreceptor response (F1) and the neuronal signaling of both second-order lamina neurons (2F1) and of the neurons which generate the 2F1+2F2 signal in frequency-tagged steady-state visually evoked potentials.

Both kinase inhibitors LRRK2-IN-1 and BMPPB-32 can restore contrast versus response functions in flies expressing Scer\GAL4VGlut-OK371>Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG.

Axonal transport of mitochondria is not affected in larval motor neurons expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4D42.

Climbing and flight ability are normal in flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4D42.

Aged, but not young, flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG via Scer\GAL4Ddc.PL exhibit dopamine neuron degeneration and locomotor dysfunction.

Expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PG results in a loss of electroretinogram (ERG) amplitude between 10 and 28 days of age. By 28 days of age, all components of the ERG (on-transient, maintained response and off-transient) are reduced compared to controls. As the response becomes smaller, the return to baseline takes longer.

28 day old flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PG show strong neurodegeneration throughout the retina (which is disorganised), and the medulla and lamina contain many vacuoles. The exterior surface of the eye appears normal in these flies.

Increased levels of autophagy and apoptosis are seen around the microvilli of the photoreceptor cells in 21-23 day old flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PG.

Photoreceptor mitochondria are swollen (70% increase in area) and the cristae are wider (80%) compared to controls in 28 day old flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PG.

PPL, MC and LA neurons are present in 28 day old flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PG and there is no reduction in the number of cell bodies or axon branching compared to age matched controls.

10 day old flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PG and raised under pulsed light conditions show a reduction in ERG amplitude compared to flies raised in constant darkness or constant light conditions.

Flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of either Scer\GAL4Ddc.HL9, Scer\GAL4elav.PLu, Scer\GAL4nSyb.PG, Scer\GAL4GMR.long or Scer\GAL4Act5C.PU show a significant reduction in ERG amplitude at 28 days of age compared to 3 days of age.

Flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4NP5214 show no significant difference in ERG amplitude at 3 and 28 days of age.

Overexpression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG in dopaminergic neurons, under the control of Scer\GAL4ple.PF, leads to a substantial reduction of dopamine neurons in the adult brain hemisphere.

Expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PF significantly reduces climbing ability.

Treatment of flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4Ddc.PL with 0.1% H[[2]]O[[2]] significantly decreases survival, compared with control flies and untreated Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG-Scer\GAL4Ddc.PL flies. Treatment with GW5074 significantly increases survival of Hsap\LRRK2 transgenic flies exposed to 0.1% H[[2]]O[[2]].

The addition of 1mM curcumin to the food given to Scer\GAL4Ddc.PL->Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG flies with or without 0.1% H[[2]]O[[2]] from day 1 post-eclosion results in an increase in survival. Curcumin has no effect on non-transgenic control flies. The addition of curcumin does not alter the effects of GW5074 on the lifespan of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG flies.

The addition of 0.1% H[[2]]O[[2]] from day 1 post-eclosion onwards significantly worsens the locomotor impairment seen in flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4Ddc.PL, compared with untreated transgenic flies. Treatment with 5υM GW5074 or 1mM curcumin improves but does not fully reverse the locomotor impairment seen in these flies.

Treatment of flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4Ddc.PL with 0.1% H[[2]]O[[2]] induces loss of DA neurons. Treatment with 0.1% H[[2]]O[[2]] for 4 weeks results in only one third of DA neurons surviving in Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG transgenic flies compared with untreated non-transgenic flies. The DA neurons in protocerebral posterior medial 1/2 clusters are significantly reduced by exposure to H[[2]]O[[2]] insult. Treatment with 5υM GW5074 or 1mM curcumin in the food from day 1 post-eclosion throughout the lifetime of Scer\GAL4Ddc.PL-->Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG suppresses the loss of ple-positive neurons.

Overexpression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG pre- or post-synaptically (under the control of Scer\GAL4elav-C155 or Scer\GAL4Mhc.PW, respectively) results in a reduction in the total number of type I boutons on muscle 6/7 from the A3 segment. In addition, neuromuscular junction length and branch number are decreased by 30%. Separate quantification of type Ib versus type Is boutons on muscle 6/7 reveals a similar degree (20%) of decrease in the number of each type of bouton.

Neuronal expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4elav-C155 leads to a significant increase in mEJC frequency. However, quantal content is decreased in these flies. EJC amplitude and quantal content are not significantly changed in Scer\GAL4Mhc.PW>Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG animals.

Expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4GMR.PF results in retinal degeneration by 3 weeks after eclosion.

Expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG driven by Scer\GAL4Ddc.PL causes early mortality and locomotion impairment.

Expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4Ddc.PL leads to selective loss of dopaminergic neurons.

Treatment of flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG driven by Scer\GAL4Ddc.PL with L-DOPA significantly improves their locomotor activity, but it does not prevent the loss of dopaminergic neurons.

Expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG driven by Scer\GAL4elav.PU causes late-onset locomotion impairment, shortened lifespan and selective loss of dopaminergic neurons.

External Data
Interactions
Show genetic interaction network for Enhancers & Suppressors
Phenotypic Class
Enhanced by
Suppressed by
Statement
Reference
NOT suppressed by
Phenotype Manifest In
Suppressed by
NOT suppressed by
Suppressor of
Additional Comments
Genetic Interactions
Statement
Reference
Xenogenetic Interactions
Statement
Reference

Co-expression of Hsap\SNCAIPScer\UAS.cLa significantly increases survival, improves locomotor impairment, and partially rescues dopaminergic neuron degeneration caused by expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4Ddc.PU.

The dopamine neuron degeneration and locomotor dysfunction observed in aged flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG via Scer\GAL4Ddc.PL are completely rescued by co-expression of Hsap\RPS15T136A.Scer\UAS but not Hsap\RPS15Scer\UAS.cMa.

Lrrke03680/+ partially suppresses the reduction in electroretinogram amplitude seen in 28 day old flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PG.

Simultaneous co-expression of both eagDN.EKI.Scer\UAS and ShDN.EKI.Scer\UAS.T:Avic\GFP-GL enhances the progressive reduction in electroretinogram (ERG) amplitude which is seen in flies expressing Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG under the control of Scer\GAL4ple.PG, such that the triple mutant flies show a significant reduction in ERG amplitude at 10 days of age.

Co-expression of Hsap\ARFGAP1Scer\UAS.T:Ivir\HA1 with Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG in dopaminergic neurons, under the control of Scer\GAL4ple.PF, significantly prevents the loss of dopamine neurons in PAL and PPM1/2 but not PPM3 or PPL1 clusters.

Co-expression of Hsap\ARFGAP1Δ64.Scer\UAS.T:Ivir\HA1 with Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG in dopaminergic neurons, under the control of Scer\GAL4ple.PF, rescues dopaminergic neuronal loss in the PPM1/2 but does not significantly rescue in the other dopaminergic clusters.

Co-expression of either Hsap\ARFGAP1Scer\UAS.T:Ivir\HA1 or Hsap\ARFGAP1Δ64.Scer\UAS.T:Ivir\HA1 in dopaminergic neurons, under the control of Scer\GAL4ple.PF, rescues the climbing defect seen in Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG-expressing flies.

Co-expression of Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG rescues the eye defects seen upon expression of Hsap\ARFGAP1Scer\UAS.T:Ivir\HA1 under the control of Scer\GAL4GMR.PF.

Complementation and Rescue Data
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Mutant
Wild-type
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External Crossreferences and Linkouts ( 0 )
Synonyms and Secondary IDs (3)
Reported As
Symbol Synonym
Hsap\LRRK2G2019S.Scer\UAS.T:Zzzz\FLAG
Hsap\LRRK2G2019S.UAS.Tag:FLAG
Name Synonyms
Secondary FlyBase IDs
    References (15)