PLOS Biology: New Articles

1. Gap junctions allow transfer of metabolites between germ cells and somatic cells to promote germ cell growth in the <i>Drosophila</i> ovary

   by Caroline Vachias, Camille Tourlonias, Louis Grelée, Nathalie Gueguen, Yoan Renaud, Parvathy Venugopal, Graziella Richard, Pierre Pouchin, Emilie Brasset, Vincent Mirouse

   Gap junctions allow the exchange of small molecules between cells. How this function could be used to promote cell growth is not yet fully understood. During Drosophila ovarian follicle development, germ cells, which are surrounded by epithelial somatic cells, undergo massive growth. We found that this growth depends on gap junctions between these cell populations, with a requirement for Innexin4 and Innexin2, in the germ cells and the somatic cells, respectively. Translatomic analyses revealed that somatic cells express enzymes and transporters involved in amino acid metabolism that are absent in germ cells. Among them, we identified a putative amino acid transporter required for germline growth. Its ectopic expression in the germline can partially compensate for its absence or the one of Innexin2 in somatic cells. Moreover, affecting either gap junctions or the import of some amino acids in somatic cells induces P-bodies in the germ cells, a feature usually associated with an arrest of translation. Finally, in somatic cells, innexin2 expression and gap junction assembly are regulated by the insulin receptor/PI3K kinase pathway, linking the growth of the two tissues. Overall, these results support the view that metabolic transfer through gap junction promotes cell growth and illustrate how such a mechanism can be integrated into a developmental program, coupling growth control by extrinsic systemic signals with the intrinsic coordination between cell populations.
2. Capsid transfer of the retrotransposon Copia controls structural synaptic plasticity in <i>Drosophila</i>

   by P. Githure M’Angale, Adrienne Lemieux, Yumeng Liu, Shuhao Wang, Max Zinter, Gimena Alegre, Alfred Simkin, Vivian Budnik, Brian A. Kelch, Travis Thomson

   Transposons are parasitic genome elements that can also serve as raw material for the evolution of new cellular functions. However, how retrotransposons are selected and domesticated by host organisms to modulate synaptic plasticity remains largely unknown. Here, we show that the Ty1 retrotransposon Copia forms virus-like capsids in vivo and transfers between cells. Copia is enriched at the Drosophila neuromuscular junction (NMJ) and transported across synapses, and disrupting its expression promotes both synapse development and structural synaptic plasticity. We show that proper synaptic plasticity is maintained in Drosophila by the balance of Copia and the Arc1 (activity-regulated cytoskeleton-associated protein) homolog. High-resolution cryogenic-electron microscopy imaging shows that the structure of the Copia capsid has a large capacity and pores like retroviruses but is distinct from domesticated capsids such as dArc1. Our results suggest a fully functional transposon mediates synaptic plasticity, possibly representing an early stage of domestication of a retrotransposon.
3. The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson’s disease

   by Lijun Dai, Jiannan Wang, Lanxia Meng, Xingyu Zhang, Tingting Xiao, Min Deng, Guiqin Chen, Jing Xiong, Wei Ke, Zhengyuan Hong, Lihong Bu, Zhentao Zhang

   Parkinson’s disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1–LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.
4. GitHub enables collaborative and reproducible laboratory research

   by Katharine Y. Chen, Maria Toro-Moreno, Arvind Rasi Subramaniam

   GitHub, a platform widely used in software development, offers a robust framework for documenting all activities of laboratory research projects. This Community Page highlights the benefits of, and provides guidance for, incorporating the GitHub ecosystem into “wet” lab workflows.
5. Toll-1-dependent immune evasion induced by fungal infection leads to cell loss in the <i>Drosophila</i> brain

   by Deepanshu N. D. Singh, Abigail R. E. Roberts, Xiaocui Wang, Guiyi Li, Enrique Quesada Moraga, David Alliband, Elizabeth Ballou, Hung-Ji Tsai, Alicia Hidalgo

   Fungi can intervene in hosts’ brain function. In humans, they can drive neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. The mechanism underlying innate immunity to fungi is well-known and universally conserved downstream of shared Toll/TLR receptors, which via the adaptor MyD88 and the transcription factor Dif/NFκB, induce the expression of antimicrobial peptides (AMPs). However, in the brain, Toll-1 could also drive an alternative pathway via Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. Here, we show that exposure to the fungus Beauveria bassiana reduced fly life span, impaired locomotion and caused neurodegeneration. Beauveria bassiana entered the Drosophila brain and induced the up-regulation of AMPs, and the Toll adaptors wek and sarm, within the brain. RNAi knockdown of Toll-1, wek or sarm concomitantly with infection prevented B. bassiana-induced cell loss. By contrast, over-expression of wek or sarm was sufficient to cause neuronal loss in the absence of infection. Thus, B. bassiana caused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. A similar activation of Sarm downstream of TLRs upon fungal infections could underlie psychiatric and neurodegenerative diseases in humans.