TY  - JOUR
AU  - Richard, Mélisande
AU  - Doubková, Karolína
AU  - Nitta, Yohei
AU  - Kawai, Hiroki
AU  - Sugie, Atsushi
AU  - Tavosanis, Gaia
TI  - A quantitative model of sporadic axonal degeneration in the Drosophila visual system.
JO  - The journal of neuroscience
VL  - 42
IS  - 24
SN  - 0270-6474
CY  - Washington, DC
PB  - Soc.
M1  - DZNE-2022-00665
SP  - 4937-4952
PY  - 2022
N1  - CC BY
AB  - In human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modelling 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 ageing 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 towards degeneration. Utilizing the ordered distribution of Drosophila photoreceptors 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 shedding light on key steps in the etiology of non-familial cases of neurodegenerative diseases.
KW  - Animals
KW  - Axons: physiology
KW  - Drosophila: physiology
KW  - Drosophila Proteins: genetics
KW  - Female
KW  - Neurodegenerative Diseases
KW  - Synapses: physiology
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9188428
C6  - pmid:35534228
DO  - DOI:10.1523/JNEUROSCI.2115-21.2022
UR  - https://pub.dzne.de/record/163996
ER  -