Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells.

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear. Here, we show that p53 maintains quiescence by inducing fatty-acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPARα to upregulate FAO genes. Dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumor initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention.

A Drosophila model for primary coenzyme Q deficiency and dietary rescue in the developing nervous system.

Coenzyme Q (CoQ) or ubiquinone is a lipid component of the electron transport chain required for ATP generation in mitochondria. Mutations in CoQ biosynthetic genes are associated with rare but severe infantile multisystemic diseases. CoQ itself is a popular over-the-counter dietary supplement that some clinical and rodent studies suggest might be beneficial for neurodegenerative diseases. Here, we identify mutations in the Drosophila qless gene, which encodes an orthologue of the human PDSS1 prenyl transferase that synthesizes the isoprenoid side chain of CoQ. We show that neurons lacking qless activity upregulate markers of mitochondrial stress and undergo caspase-dependent apoptosis. Surprisingly, even though experimental inhibition of caspase activity did not prevent mitochondrial disruption, it was sufficient to rescue the size of neural progenitor clones. This demonstrates that, within the developing larval CNS, qless activity is required primarily for cell survival rather than for cell growth and proliferation. Full rescue of the qless neural phenotype was achieved by dietary supplementation with CoQ4, CoQ9 or CoQ10, indicating that a side chain as short as four isoprenoid units can provide in vivo activity. Together, these findings show that Drosophila qless provides a useful model for studying the neural effects of CoQ deficiency and dietary supplementation.