Publications

Studies of the familial Parkinson disease-related proteins PINK1 and Parkin have demonstrated that these factors promote the fragmentation and turnover of mitochondria following treatment of cultured cells with mitochondrial depolarizing agents. Whether PINK1 or Parkin influence mitochondrial quality control under normal physiological conditions in dopaminergic neurons, a principal cell type that degenerates in Parkinson disease, remains unclear. To address this matter, we developed a method to purify and characterize neural subtypes of interest from the adult Drosophila brain. Using this method, we find that dopaminergic neurons from Drosophila parkin mutants accumulate enlarged, depolarized mitochondria, and that genetic perturbations that promote mitochondrial fragmentation and turnover rescue the mitochondrial depolarization and neurodegenerative phenotypes of parkin mutants. In contrast …

The tumor suppressor Adenomatous polyposis coli (APC) negatively regulates Wnt signaling through its activity in the destruction complex. APC binds directly to the main effector of the pathway, β-catenin (βcat, Drosophila Armadillo), and helps to target it for degradation. In vitro studies demonstrated that a nonphosphorylated 20-amino-acid repeat (20R) of APC binds to βcat through the N-terminal extended region of a 20R. When phosphorylated, the phospho-region of an APC 20R also binds βcat and the affinity is significantly increased. These distinct APC–βcat interactions suggest different models for the sequential steps of destruction complex activity. However, the in vivo role of 20R phosphorylation and extended region interactions has not been rigorously tested. Here we investigated the functional role of these molecular interactions by making targeted mutations in Drosophila melanogaster APC2 that …

The recent discovery of RNA interference (RNAi) has revolutionized our understanding of RNA biology and genetic regulation. Researchers have mounted an international
effort to elucidate RNAi pathways in order to harness them for their therapeutic potential.
Caenorhabditis elegans, a model organism widely used to study RNAi, has distinct silencing
pathways for interfering RNAs derived from endogenous and exogenous sources. Although
the exogenous RNAi pathway has been largely mapped, endogenous RNAi pathways remain
largely uncharacterized. In particular, RNA Helicase A (RHA-1) is an actor in endogenous
RNAi whose function remains unknown. C. elegans deficient in RHA-1 exhibit a phenotype
similar to animals deficient in ERI-1, a component of the endogenous 26G RNAi pathway.
To test whether RHA-1 works in the 26G pathway, we measured changes in 26G interfering
RNAs in worms deficient in RHA-1, ERI-1, and both RHA-1 and ERI-1. The preliminary
data indicates that RHA-1 is not involved in 26G RNA biogenesis, but may be working
further downstream in the pathway.