Mutations in the genes encoding biosynthetic enzymes for CoenzymeQ (CoQ; also known as ubiquinone), a lipid component of the mitochondrial electron transport chain, result in primary CoQ-deficiency diseases. These are rare but severe conditions that typically present in early infancy and affect multiple organs, particularly those with high-energy demands such as brain, muscle and kidney. Thus far, disease-associated mutations in humans have been mapped to four of the nine CoQ biosynthetic genes that were originally identified by genetic studies in yeast. Two of these – prenyl diphosphate synthase subunit 1 (PDSS1) and prenyl diphosphate synthase subunit 2 (PDSS2) – encode subunits of the transferase that synthesizes the isoprenoid side chain of CoQ. Recessive point mutations in the catalytic domain of PDSS1 are associated with early-onset encephaloneuropathy, deafness and livedo reticularis. Compound heterozygous mutations in PDSS2 have been linked to nephropathy, myopathy and a progressive neurodegenerative disease known as Leigh syndrome. However, the rarity of identified human mutations in PDSS1, PDSS2 and other genes in the CoQ biosynthetic pathway means that it has been difficult to develop efficient CoQ-supplementation regimes and other treatments for primary CoQ deficiencies. In addition, CoQ is thought to provide benefit for neurodegenerative diseases when provided as a dietary supplement, although little is known about how its effects are mediated.

In this study, the authors establish a Drosophila model for primary CoQ-deficiency disease in the developing central nervous system (CNS), and demonstrate rescue of the mutant phenotype by dietary CoQ supplementation. Flies carrying recessive mutations in qless, the Drosophila orthologue of human PDSS1, are isolated and their phenotypes assessed by examining neural progenitor clones in the developing CNS. Lack of qless activity leads to mitochondrial disruption and to dramatically reduced numbers of neurons. Expression of a caspase inhibitor in qless-mutant clones does not ameliorate the mitochondrial defects but does restore neuronal number. This finding indicates that the primary function of qless is to promote the survival of neurons, rather than their proliferation. The addition of CoQ or its derivatives to Drosophila food fully rescues mitochondrial disruption, cell survival and all other aspects of the qless neuronal phenotype. This establishes in an intact developing animal that a primary deficiency in CoQ biosynthesis in the CNS can be corrected by supplementing the diet with CoQ.

This new genetic model for primary CoQ deficiency in the developing CNS of Drosophila will be useful for studying the mechanism of action of CoQ and its derivatives. In turn, this might help to guide the optimization of new CoQ-based treatment regimes. For example, a crucial issue in human primary CoQ deficiencies is that the initial diagnosis and subsequent treatment are often made neonatally, only after severe organ damage has already occurred. Studying both Drosophila and rodent models provides the opportunity to optimize prophylactic CoQ maternal dietary supplementation regimes, either to be implemented for all expectant mothers or more selectively on the basis of genetic screening. The Drosophila qless rescue system also provides a robust in vivo bioassay for testing the relative efficacies of CoQ and its derivatives, which are sold as popular dietary supplements. In addition, future research involving qless together with Drosophila models of Parkinson’s or Huntington’s diseases might shed light on the claims that CoQ supplementation delays or reduces the symptoms of some human neurodegenerative diseases.

2010