Dopaminergic expression of the Parkinsonian gene LRRK2-G2019S leads to non-autonomous visual neurodegeneration, accelerated by increased neural demands for energy

Abstract

Parkinson's disease (PD) is associated with loss of dopaminergic signalling, and affects not just movement, but also vision. As both mammalian and fly visual systems contain dopaminergic neurons, we investigated the effect of LRRK2 mutations (the most common cause of inherited PD) on Drosophila electroretinograms (ERGs). We reveal progressive loss of photoreceptor function in flies expressing LRRK2-G2019S in dopaminergic neurons. The photoreceptors showed elevated autophagy, apoptosis and mitochondrial disorganization. Head sections confirmed extensive neurodegeneration throughout the visual system, including regions not directly innervated by dopaminergic neurons. Other PD-related mutations did not affect photoreceptor function, and no loss of vision was seen with kinase-dead transgenics. Manipulations of the level of Drosophila dLRRK suggest G2019S is acting as a gain-of-function, rather than dominant negative mutation. Increasing activity of the visual system, or of just the dopaminergic neurons, accelerated the G2019S-induced deterioration of vision. The fly visual system provides an excellent, tractable model of a non-autonomous deficit reminiscent of that seen in PD, and suggests that increased energy demand may contribute to the mechanism by which LRRK2-G2019S causes neurodegeneration.

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.…”

iFly: The eye of the fruit fly as a model to study autophagy and related trafficking pathways

“…For example, dopaminergic cell-specific expression of a mutant form of the Parkinson's disease related protein LRRK2 induced ectopic autophagy activation and cell loss in the retina, even though retinal cells do not have direct dopaminergic input (Hindle et al, 2013). This phenotype suggests that the disease is able to spread across multiple cells in the Drosophila nervous system, possibly in a similar way as a-synuclein, which may show a prion-like cell-to-cell spread in human patients suffering from dementia with Lewy bodies or Parkinson's disease .…”

Modeling LRRK2 Pathobiology in Parkinson’s Disease: From Yeast to Rodents

“…Collectively, the overexpression of pathogenic dLRRK, human WT LRRK2, and to a more severe extent, G2019S, Y1699C, or G2385R mutant human LRRK2, induces an adult-onset and progressive loss of dopaminergic neurons, early mortality and impaired motor function that could be attenuated by treatment with L-DOPA, and exacerbated by the mitochondrial toxin rotenone (Imai et al 2008;Liu et al 2008;Ng et al 2009;Venderova et al 2009;Liu et al 2011;MacLeod et al 2013). Intriguingly, a recent study demonstrated that G2019S LRRK2 expression confined to dopaminergic neurons resulted in neurodegeneration throughout the fly visual system, including within brain regions lacking obvious dopaminergic innervation (Hindle et al 2013). G2019S LRRK2 expression in dopaminergic neurons caused a non-cell autonomous progressive loss of photoreceptor function and retinal neurodegeneration accompanied by mitochondrial dysfunction, autophagic vacuole accumulation, and apoptosis in the vicinity of photoreceptors.…”

“…Expression of additional PD-associated LRRK2 mutants (I1122V, R1441C, Y1387C, Y1699C, I1915T, I2020T, and G2385R) failed to similarly impair photoreceptor function. Furthermore, the visual deficits induced by G2019S LRRK2 expression were kinase-dependent as revealed by simultaneous introduction of the kinase-inactive variant, K1906M, which disrupts the ATP-binding pocket within the kinase domain (Hindle et al 2013). Interestingly, increasing the demands on the visual system to adapt, or increasing the activity of dopaminergic neurons, accelerates the decline in visual function induced by G2019S LRRK2 expression.…”