A Quantitative Model of Sporadic Axonal Degeneration in the Drosophila Visual System

Abstract

In human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modeling early degenerative events in Drosophila adult photoreceptor cells. Thanks to the stereotypy of their axonal projections, this system delivers quantitative data on sporadic and progressive axonal degeneration of photoreceptor cells. Using this method, we show that exposure of adult female flies to a constant light stimulation for several days overcomes the intrinsic resilience of R7 photoreceptors and leads to progressive axonal degeneration. This was not associated with apoptosis. We furthermore provide evidence that loss of synaptic integrity between R7 and a postsynaptic partner preceded axonal degeneration, thus recapitulating features of human neurodegenerative diseases. Finally, our experiments uncovered a role of postsynaptic partners of R7 to initiate degeneration, suggesting that postsynaptic cells signal back to the photoreceptor to maintain axonal structure. This model can be used to dissect cellular and circuit mechanisms involved in the early events of axonal degeneration, allowing for a better understanding of how neurons cope with stress and lose their resilience capacities. SIGNIFICANCE STATEMENT Neurons can be active and functional for several years. In the course of aging and in disease conditions leading to neurodegeneration, subsets of neurons lose their resilience and start dying. What initiates this turning point at the cellular level is not clear. Here, we developed a model allowing to systematically describe this phase. The loss of synapses and axons represents an early and functionally relevant event toward degeneration. Using the ordered distribution of Drosophila photoreceptor axon terminals, we assembled a system to study sporadic initiation of axon loss and delineated a role for non-cell-autonomous activity regulation in the initiation of axon degeneration. This work will help shed light on key steps in the etiology of nonfamilial cases of neurodegenerative diseases.

Allnighter pseudokinase-mediated feedback links proteostasis and sleep in Drosophila

“…Induction of the aln phenotype by the switch from LD to LL suggests an involvement of the circadian system, in line with the disruption of the circadian clock observed under sustained high light intensities 27 . Therefore, we wondered whether the Aln LL phenotypes may be mimicked in the per 01 circadian clock mutant.…”

Drosophilamodel to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy

“…To compare the number of retinal axon terminals–R7 axons–between genotypes, we used a previously developed automated method, MeDUsA ( me thod for the quantification of d egeneration us ing fly a xons) (Nitta et al, 2023). We have assessed the extent of their reduction from the total axonal terminal count, thereby determining the degree of axonal terminal degeneration (Nitta et al, 2023; Richard et al, 2022). Our results showed that the dOPA1 knockdown caused axonal degeneration one day after eclosion, further decreasing one week later (Figure 3B–E, quantification in 3F).…”

“…Drosophila photoreceptors type R7/8 extend their retinal axons from the retina directly into the brain, forming synapses in the second optic ganglion medulla via the chiasma (Figure 1A), having potential application as a model for mammalian photoreceptors and RGCs. Based on this, we aimed to develop an experimental model for observing and quantifying degeneration in the Drosophila retinal axon (Nitta et al, 2023; Richard et al, 2022).…”

“…In this study, we defined the retinal axons of Drosophila as analogous to the human optic nerve. Based on this, we aimed to develop an experimental model for observing and quantifying degeneration in the Drosophila retinal axon (Nitta et al, 2023; Richard et al, 2022).…”

Learning and memory in Drosophila: Role of white mutation

“…Соответственно, мухи wимеют повышенную светочувствительность (Wu, Wong 1977), но недостаточную остроту зрения (Kalmus 1943). Другая функция белка white заключается в защите фоторецепторов сетчатки от чрезмерного воздействия света (Richard et al 2022). Данный ген экспрессируется в основном в пигментных клетках глаз, мальпигиевых канальцах и семен-никах (Evans et al 2008;Sullivan, Sullivan 1975).…”