MARTIN, J.-R. | bioRxiv Science

bioRxiv2020

ninaD regulates cholesterol homeostasis from the midgut which protects against neurodegeneration

Cholesterol is crucial to maintain normal cellular function. In human, it has also been involved in various neurodegeneration processes, as Niemann-Pick and Alzheimer diseases. Recently, we have identified a small nucleolar RNA (jouvence) required in the epithelial cells of the gut (enterocytes), and showed that its overexpression extends lifespan. A transcriptomic analysis has revealed a deregulation of several genes in jouvence mutants. Among them, ninaD encoding a mammalian homolog to class B Scavenger receptor is importantly upregulated. In Drosophila, ninaD is required for the uptake of the dietary carotenoid, used for the formation of rhodopsin. Here, we show that jouvence-deleted flies are deficient in cholesterol-ester, as well as old flies present neurodegenerative lesions. Restoring ninaD mRNA expression level in enterocytes restores the metabolic cholesterol-ester level, prevents neurodegeneration and extends lifespan, revealing a gut-brain axis. Our studies demonstrates that ninaD is a central regulator of cholesterol homeostasis and a longevity-promoting factor.

neuroscience↗

bioRxiv2020

jouvence, a new human H/ACA snoRNA involves in the control of cell proliferation and differentiation

Small nucleolar RNAs (snoRNAs) are non-coding RNAs conserved from archeobacteria to mammals. In humans, various snoRNAs have been associated with pathologies as well as with cancer. Recently in Drosophila, a new snoRNA named jouvence has been involved in lifespan. Since snoRNAs are well conserved through evolution, both structurally and functionally, jouvence orthologue has been identified in human, allowing hypothesizing that jouvence could display a similar function (increasing healthy lifespan) in human. Here, we report the characterization of the human snoRNA-jouvence, which was not yet annotated in the genome. We show, both in stably cancerous cell lines and in primary cells, that its overexpression stimulates the cell proliferation. In contrast, its knockdown, by siRNA leads to an opposite phenotype, a decrease in cell proliferation. Transcriptomic analysis reveals that overexpression of jouvence leads to a dedifferentiation signature of the cells, a cellular effect comparable to rejuvenation. Inversely, the knockdown of jouvence leads to a decrease of genes involved in ribosomes biogenesis and spliceosome in agreement with the canonical role of a H/ACA box snoRNA. In this context, jouvence could represent a now tool to fight against the deleterious effect of aging, as well as a new target in cancer therapy.

genetics↗