Abnormal visual gain control in a Parkinson's disease model.
Our understanding of Parkinson's disease (PD) has been revolutionized by the discovery of disease-causing genetic mutations. The most common of these is the G2019S mutation in the LRRK2 kinase gene, which leads to increased kinase activity. However, the link between increased kinase activity and PD is unclear. Previously, we showed that dopaminergic expression of the human LRRK2-G2019S transgene in flies led to an activity-dependent loss of vision in older animals and we hypothesized that this may have been preceded by a failure to regulate neuronal activity correctly in younger animals. To test this hypothesis, we used a sensitive measure of visual function based on frequency-tagged steady-state visually evoked potentials. Spectral analysis allowed us to identify signals from multiple levels of the fly visual system and wild-type visual response curves were qualitatively similar to those from human cortex. Dopaminergic expression of hLRRK2-G2019S increased contrast sensitivity throughout the retinal network. To test whether this was due to increased kinase activity, we fed Drosophila with kinase inhibitors targeted at LRRK2. Contrast sensitivity in both day 1 and day 14 flies was normalized by a novel LRRK2 kinase inhibitor 'BMPPB-32'. Biochemical and cellular assays suggested that BMPPB-32 would be a more specific kinase inhibitor than LRRK2-IN-1. We confirmed this in vivo, finding that dLRRK(-) null flies show large off-target effects with LRRK2-IN-1 but not BMPPB-32. Our data link the increased Kinase activity of the G2019S-LRRK2 mutation to neuronal dysfunction and demonstrate the power of the Drosophila visual system in assaying the neurological effects of genetic diseases and therapies.
Department of Biology and.
Farinaz
F
Afsari
Neuroscience Drug Discovery DK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
Kenneth V
KV
Christensen
Neuroscience Drug Discovery DK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
Garrick Paul
GP
Smith
Neuroscience Drug Discovery DK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
Morten
M
Hentzer
Department of Biology and.
Olivia M
OM
Nippe
Department of Biology and.
Christopher J H
CJ
Elliott
Department of Psychology, University of York, YO1 5DD York, UK wade@wadelab.net.
Alex R
AR
Wade
D000818:Animals; D015350:Contrast Sensitivity / Q000187:drug effects; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000502:physiology*; D005074:Evoked Potentials, Visual / Q000187:drug effects; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000503:physiopathology*; D010470:Perceptual Masking; D017956:Photoreceptor Cells, Invertebrate / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014785:Vision, Ocular / Q000187:drug effects / Q000502:physiology*
D047428:Protein Kinase Inhibitors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases