Tenedini, F. | bioRxiv Science

bioRxiv2024

Axon length-dependent synapse loss is mediated by neuronal cytokine-induced glial phagocytosis

Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors, but our understanding of this specific vulnerability is limited. Using Drosophila larval class IV dendrite arborization (C4da) neurons, we found that neuronal activation of the integrated stress response (ISR) induces axon length-dependent degeneration (LDD). We identified the Interleukin-6 homologue unpaired 3 (upd3) as both necessary and sufficient for LDD in C4da neurons. Upd3 recruits glial cells to phagocytose presynapses preferentially on neurons with long axons, revealing an intrinsic axon length-dependent vulnerability to glia-mediated presynapse removal. Finally, we found that axon length-dependent presynapse loss in fly models of human NDDs utilized this pathway. Altogether, our studies identify inflammatory cytokine signaling from neurons to glia as a key determinant in axon length-dependent vulnerability. One-Sentence SummarySensory neurons exhibit intrinsic length-dependent vulnerability to presynapse removal driven by cytokine activation of glia.

neuroscience↗

bioRxiv2017

Artificial anion-conducting channelrhodopsins with tuned spectra, modified kinetics and enhanced light sensitivity

Genetic engineering of natural light-gated ion channels has proven a powerful way to generate optogenetic tools for a wide variety of applications. In recent years, blue light-activated engineered anion conducting channelrhodopsins (eACRs) have been developed, improved, and were successfully applied in vivo. We asked whether the approaches used to create eACRs can be transferred to other well-characterized cation-conducting channelrhodopsins (CCRs) to obtain eACRs with a broad spectrum of biophysical properties. We generated 22 variants using two conversion strategies applied to 11 CCRs and screened them for membrane expression, photocurrents and anion selectivity. We obtained two novel eACRs, Phobos and Aurora, with blue-and red-shifted action spectra and photocurrents similar to existing eACRs. Furthermore, step-function mutations greatly enhanced the cellular operational light sensitivity due to a slowed-down photocycle. These bistable eACRs can be reversibly toggled between open and closed states with brief light pulses of different wavelengths. All new eACRs reliably inhibited action potential firing in pyramidal CA1 neurons. In Drosophila larvae, eACRs conveyed robust and specific light-dependent inhibition of locomotion and nociception.

neuroscience↗