LRRK2(I2020T) functional genetic interactors that modify eye degeneration and dopaminergic cell loss in Drosophila
Open accessAbstract
Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta is the primary cause for motor symptoms observed in Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most commonly linked contributor to familial PD. LRRK2 is suggested to be involved in a wide variety of cellular processes, but deciphering its role in the pathogenesis of PD has been difficult. Modelling PD in rodents has been a persistent challenge for the field. However, the fruit fly has been exploited to recapitulate PD gene related dopaminergic cell loss. Using the GAL4-UAS system and established models of hLRRK2 induced eye degeneration in Drosophila, we conducted an unbiased suppressor/enhancer screen to uncover genetic modifiers of LRRK2. We have identified 36 candidate interactors that modify LRRK2 induced toxicity in the Drosophila eye. Importantly, we determined that a subset of these interactors also modified hLRRK2(I2020T) induced dopaminergic neuronal loss in the fly brain and uncovered 16 candidates that modify dopaminergic cell loss. Our results suggest LRRK2 may be involved in a wide variety of cellular processes and the results from this screen provide an important genetic resource for further evaluation of LRRK2 function.
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Using an hLRRK2-induced eye degeneration model in Drosophila, genetic modifiers of LRRK2 were screened, and Scar/WAVE was found to be a genetic interactor of LRRK2.
“Using an hLRRK2-induced eye degeneration model in Drosophila, genetic modifiers of LRRK2 were screened, and Scar/WAVE was found to be a genetic interactor of LRRK2168.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [168]
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Cites
D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease
Tieu, K., Perier, C., Caspersen, C., Teismann, P., Wu, D.-C., Yan, S.-D., Naini, A., Vila, M., Jackson-Lewis, V., Ramasamy, R., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200318797 · Cited by 497 · see citing works
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Kim, K. S., Marcogliese, P. C., Yang, J., Callaghan, S. M., Resende, V., Abdel-Messih, E., Marras, C., Visanji, N. P., Huang, J., Schlossmacher, M. G., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718946115 · Cited by 111 · see citing works
Self-citationThe WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Marcogliese, P. C., Abuaish, S., Kabbach, G., Abdel-Messih, E., Seang, S., Li, G., Slack, R. S., Haque, M. E., Venderova, K., & Park, D. S.
- Affiliations
- University of Ottawa (CA)
- United Arab Emirates University (AE)
- Department of Biopharmaceutical Sciences, Keck Graduate Institute, Claremont, CA, USA
- Corresponding author
- Park, David S.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-02-02
- Volume
- 26
- Issue
- 7
- Pages
- 1247-1257
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC6075539
- OpenAlex
- W2583450464
- Cited by
- 20
- References
- 1
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 5 · 2018: 6
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- LRRK2, Parkinson's disease, dopaminergic neuron loss, eye degeneration, genetic modifiers, suppressor screen, enhancer screen, Drosophila, substantia nigra pars compacta, familial Parkinson's disease, GAL4/UAS system
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Disease Models, Animal, Dopamine, Drosophila melanogaster, Epistasis, Genetic, Eye Diseases, Humans, Mice, Transgenic, Mutation, Parkinson Disease, Substantia Nigra, Protein Serine-Threonine Kinases, Drosophila Proteins, Mice, Dopaminergic Neurons
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