Abnormal visual gain control in a Parkinson's disease model

Abstract

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.

Evidence for an Optimal Algorithm Underlying Signal Combination in Human Visual Cortex

“…The white triangle contrast response function in Figure 4 c , d is shifted to the right relative to the single component (circles) function. This is a classic contrast gain control effect, reported widely in previous human SSVEP (Candy et al 2001; Busse et al 2009; Tsai et al 2012; Baker and Vilidaitė 2014), animal SSVEP (Afsari et al 2014), and single-cell (Morrone et al 1982; Carandini and Heeger 1994) studies. The white inverted triangles in Figure 4 e , f show the complementary response at the mask frequency as target contrast increases.…”

UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2 G2019S carriers and in vivo

“…The photoreceptor mitochondria are dilated and have disorganized, aberrant cristae. 11,12 We further demonstrate that UDCA exerts a beneficial effect on mitochondrial dysfunction in NM-LRRK2 G2019S and report a beneficial effect of UDCA in vivo.…”

“…11,12 Newly emerged female flies were transferred to vials of instant food (Carolina Biological Supply, Burlington, NC) containing no drug or 2.5 mM of UDCA in a pulsating light incubator at 29°C. Flies were transferred to fresh food every 2-3 days.…”

Neurodegeneration caused by LRRK2-G2019S requires Rab10 in select dopaminergic neurons

“…This permits us to analyse the effects of Rab10 manipulation in three systems: vision, a reaching movement task (proboscis extension) and sleep. We selected these systems as they are dopaminergic in both flies and mammals, and because the physiological and degenerative consequences of LRRK2 manipulations can be accurately quantified using robust, highly sensitive assays (14)(15)(16).…”

“…We found that a number of Parkinson's-mimic flies showed increased activity in the lamina neurons at 1 day old, including those expressing LRRK2-G2019S in their dopaminergic neurons using the Tyrosine Hydroxylase GAL4 (THG2 flies) (15,17). Old THG2 flies show loss of visual response, which is accelerated by a mild visual stress, achieved by keeping the flies in a 'disco-chamber' where the light is turned off every ~2 s (18).…”