Phagocytosis and self-destruction break down Drosophila sensory neuron dendrites at distinct stages of Wallerian degeneration


Importance

Nicotinamide Adenine Dinucleotide (NAD) Mutations+) biosynthetic pathway are associated with progressive neurodegeneration; neuronal damage causes rapid breakdown of damaged axons and dendrites. NAD+ Reduction is thought to underlie both types of degeneration by inducing neuronal self-destruction. Here we show that phagocytosis, instead of self-destruction, results in the degeneration of Drosophila sensory dendrites in wounds and genetic NAD+ disturbances. Mechanically, phagocytosis is induced earlier than self-destruction by these manipulations, due to exposure to phosphatidylserine on the surface of the dendrite. In addition, damaged dendrites exhibit unique calcium dynamics and only partially require the axonal death factor Axed for their self-destruction. Thus, our results suggest important contributions of phagocytosis to NAD+– related neurodegenerative diseases and highlight the difference between the degeneration of dendrites and axons.

Summary

After injury, severed dendrites and axons expose the phosphatidylserine (PS) “eat me” signal on their surface as they break down. Degeneration of injured axons is controlled by a conserved Wallerian degeneration (WD) pathway, which is believed to activate Sarm-mediated nicotinamide adenine dinucleotide (NAD)-mediated neurite self-destruction.+) exhaustion. While PS exposure of neurites is known to be affected by genetic manipulations of NAD+, how the WD pathway coordinates both exposure and self-destruction of neurites to PS and whether PS-induced phagocytosis contributes to neurite degradation in vivo remains unknown. Here we show that in Drosophila sensory dendrites, PS exposure and self-destruction are two sequential steps of WD resulting from Sarm activation. Surprisingly, phagocytosis is the primary driver of dendrite degeneration induced by both genetic NAD+ disturbances and injuries. However, unlike neurons Name loss, which triggers only PS exposure and results in phagocytosis-dependent dendrite degeneration, injury activates both PS exposure and self-destruction as two redundant means of dendrite degeneration. Moreover, the axonal death factor Axed is only partially required for the self-destruction of injured dendrites, acting in parallel with PS-induced phagocytosis. Finally, injured dendrites exhibit a unique rhythmic calcium flash that correlates with WD. Therefore, both NAD+-general related mechanisms and dendrite-specific programs govern PS exposure and self-destruction in injury-induced dendrite degeneration in vivo.

Footnotes

    • Accepted December 1, 2021.
  • Author contributions: HJ, MLS and CH designed research; HJ, MLS, AS and BW searched; HJ, MLS, AS, BW and CH provided new analytical reagents/tools; HJ, MLS and AS analyzed the data; and HJ, MLS, AS and CH wrote the article.

  • The authors declare no competing interests.

  • This article is a direct PNAS submission.

  • This article contains additional information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2111818119/-/DCSupplemental.

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