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.

A major IgE epitope-containing grass pollen allergen domain from Phl p 5 folds as a four-helix bundle.

Phl p 5, a 29 kDa major allergen from timothy grass pollen, is one of the most reactive members of group 5 allergens. Its sequence comprises two repeats of a novel alanine-rich motif (AR) whose structure and allergenic response are still mostly unknown. We report here a structural characterization of an immunodominant fragment of Phl p 5, Phl p 5(56-165) which comprises the first AR repeat. Recombinant (r)Phl p 5(56-165) was expressed in Escherichia coli, purified to homogeneity and shown to be sufficient to react with serum IgE from 90% of grass pollen allergic patients. Using NMR spectroscopy, we show conclusively that the fragment forms a compact globular domain which is, however, prone to degradation with time. The rPhl p 5(56-165) fold consists of a four-helix bundle held together by hydrophobic interactions between the aromatic rings and aliphatic side chains. This evidence gives clear indications about the structure of the full-length Phl p 5 and provides a rational basis for finding ways to stabilize the fold and designing therapeutic vaccines against grass pollen allergy.