Study reveals how a longevity gene protects brain stem cells
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A gene linked to unusually long lifespans in humans protects brain stem cells from the harmful effects of stress, according to a new study by investigators.

Neural stem/progenitor cells (NSPCs) persist over the lifespan while encountering constant challenges from age or injury-related brain environmental changes like elevated oxidative stress. But how oxidative stress regulates NSPC and its neurogenic differentiation is less clear.

Here they report that acutely elevated cellular oxidative stress in NSPCs modulates neurogenic differentiation through induction of Forkhead box protein O3 (FOXO3)-mediated cGAS/STING and type I interferon (IFN-I) responses.

Investigators show that oxidative stress activates FOXO3 and its transcriptional target glycine-N-methyltransferase (GNMT) whose upregulation triggers depletion of s-adenosylmethionine (SAM), a key co-substrate involved in methyl group transfer reactions. Mechanistically, they demonstrate that reduced intracellular SAM availability disrupts carboxymethylation and maturation of nuclear lamin, which induces the cytosolic release of chromatin fragments and subsequent activation of the cGAS/STING-IFN-I cascade to suppress neurogenic differentiation.

Together, the findings suggest the FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that regulates long-term regenerative potential.

Nature Communications
Source: https://doi.org/10.1038/s41467-020-20839-0
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