LRRK2(I2020T) functional genetic interactors that modify eye degeneration and dopaminergic cell loss in Drosophila.
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.
Department of Cellular and Molecular Medicine.|Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada.
Paul C
PC
Marcogliese
Department of Cellular and Molecular Medicine.|Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada.
Sameera
S
Abuaish
Department of Cellular and Molecular Medicine.|Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada.
Ghassan
G
Kabbach
Department of Cellular and Molecular Medicine.|Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada.
Elizabeth
E
Abdel-Messih
Department of Cellular and Molecular Medicine.|Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada.
Sarah
S
Seang
Department of Cellular and Molecular Medicine.|Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada.
Gang
G
Li
Department of Cellular and Molecular Medicine.|Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada.
Ruth S
RS
Slack
Department of Biochemistry, College of Medicine and Health Science, United Arab Emirates University, Al Ain, UAE.
M Emdadul
ME
Haque
Department of Biopharmaceutical Sciences, Keck Graduate Institute, Claremont, CA, USA.
Katerina
K
Venderova
Department of Cellular and Molecular Medicine.|Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada.
David S
DS
Park
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D004843:Epistasis, Genetic; D005128:Eye Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases
D004298:Dopamine; D029721:Drosophila Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C543697:LRRK protein, Drosophila; D017346:Protein Serine-Threonine Kinases