Glial-derived mitochondrial signals affect neuronal proteostasis and aging

Abstract

The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPR MT ), between tissues. However, these studies largely ignored nonneuronal cells of the nervous system. Here, we found that UPR MT activation in four astrocyte-like glial cells in the nematode, Caenorhabditis elegans , can promote protein homeostasis by alleviating protein aggregation in neurons. Unexpectedly, we find that glial cells use small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then affect neuron-mediated effects in organismal homeostasis and longevity.

Glial swip-10expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

“…In mammals, glia, particularly astrocytes (49), have been identified as a major source of brain Cu homeostasis, with the liver primarily serving this role in the periphery. The systemic contribution of glial swip-10 to whole body Cu(I) homeostasis parallels findings of an impact on systemic proteostasis by glia (23,24), and can be linked to our prior demonstration of systemic oxidative stress in swip-10 mutants(15). Although we did not examine Cu(II) levels, we hypothesize that due to loss of swip-10 mediated Cu(II) reduction, worms will display an increase in Cu(II) due to the lack of a significant change in total Cu, possibly contributing for some or the phenotypes documented in this study Recently, a Cu(II) specific probe, similar to CF4, has been reported(50) that we plan to utilize in future studies to explore this question.…”

“…These findings reinforce a critical role of glia in supporting neuronal health and signaling (15), and Glu-dependent neurodegeneration that can arise from disrupted glial-neuron interactions (22). Lastly, we found elevations of whole body oxidative stress as reported by the reporter gst-4:GFP, suggesting that, as seen with the systemic control of proteostasis (23,24), glial cells play an important role in the worm in limiting body-wide ROS production.…”

Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration

“…While C. elegans lack a conserved neuroinflammatory pathway and canonical glia, both important in ALS pathology, previous work in C. elegans has been able to identify a key role for the innate immune response in ALS models. Additionally, glia-like cells in C. elegans have been shown to regulate proteostasis and stress responses in neurons and could be studied in ALS models ( Veriepe et al, 2015 ; Bar-Ziv et al, 2023 ; Wang et al, 2023b ). For abnormal protein conformations and inclusions that slowly develop over time, the short lifespan of C. elegans may not be long enough to observe mature pathological species.…”

“…To directly examine the consequences of human ALS/FTLD genes, researchers can transgenically express wild-type or mutant human disease-associated genes in muscles, neurons, or throughout the C. elegans body, express individual protein domains, or replace the C. elegans homolog with a single-copy knock-in of the wild-type or mutant human gene. More recent efforts to model neurodegenerative diseases in C. elegans have included the development of a photoconvertible fluorescent protein tag to track protein dynamics in vivo ( Pigazzini and Kirstein, 2020 ), the conditional expression or inducible aggregation of neurotoxic proteins in aging ( Lim et al, 2020 ), the use of natural genetic variation to study resistance and resilience to protein aggregation in disease ( Alexander-Floyd et al, 2020 ), the study of synergies between distinct pathological proteinopathies ( Benbow et al, 2020 ; Latimer et al, 2022 ), the exploration of glia–neuron communication in protein quality control ( Bar-Ziv et al, 2023 ), and the development of models to study prion-like seeding or spread of disease-causing proteins in neurons ( Gallrein et al, 2021 ; Zanier et al, 2021 ). These approaches may inspire future ALS/FTLD models in C. elegans .…”

Methionine cycle in a pair of serotonergic neurons regulates diet-dependent behavior and longevity through a neuron-gut signaling

“…So, like mammals, the worms are entirely dependent on their bacterial diet for B12 supply. Additionally, due to the availability of diverse genetic, biochemical and cell biology tools, it serves as a popular model system for the exploration of evolutionarily conserved genetic pathways regulating cellular stress responses, diseases as well as inter-tissue crosstalk (Van Pelt and Truttmann 2020;Rodriguez et al 2013;Durieux, Wolff, and Dillin 2011;Taylor and Dillin 2013;Berendzen et al 2016;Bar-Ziv et al 2023;Miller et al 2022;Burkewitz et al 2015;Miller et al 2020).…”