Neurodegeneration and Development

in Drosophila

We are interested in understanding mechanisms underlying neurodegenerative diseases using Drosophila as a model system, and in ultimately translating our findings to human studies. Our current focus is on Alzheimer's disease (AD) and Parkinson's disease (PD), which are the two most common neurodegenerative disorders affecting half of the population over the age of 85. Currently, no treatment can halt the progress of these diseases. Much of our work aims to create disease models, study functions of disease genes during development, and to identify new genes implicated in disease pathways through genome-wide screens. Our goals are to understand disease pathogenesis, identify new diagnostic tools and therapeutic targets.

One of the pathological hallmarks of AD is the accumulation of amyloid plaques consisting of a toxic peptide known as A-beta. A-beta is generated from a transmembrane protein, the Amyloid Precursor Protein (APP), through the action of two proteases, one of which is gamma secretase. Gamma secretase is contained in a large multi-protein complex including Presenilin. Mutations in APP, Presenilin1 and Presenilin 2 mediate familial, early-onset AD with 100% penetrance. We are interested in understanding the regulation of APP cleavage by gamma-secretase, APP steady state levels and the fate of the APP intracellular domain (AICD).   Toward this goal, we have developed an in vivo reporter system to identify these regulators through function-based genetic screen in the eye (Guo et al, HMG 2003; Gross et al, 2008). We have identified multiple enhancers and suppressors of this reporter via unbiased genetic screens and candidate testing. One of the modifiers is ubiquilin. We have shown that ubiquilin antagonizes presenilin function and promotes neurodegeneration (Ganguly et al, HMG, 2008). We are in the process of characterizing the functions of other modifiers, which include a microRNA and protein coding genes with essential functions during neurodevelopment.

Recently, six genes definitively linked to familial PD have been identified. We have shown that flies lacking one of these, pink1, result in defects in mitochondrial morphology and function, increased sensitivity to stress and reduced life span. Remarkably, overexpression of human PINK1 rescues cellular defects due to loss of pink1 function in flies. In addition, pink1 acts in the same genetic pathway as parkin, another gene linked to familial PD (Clark et al, Nature 2006; Dodson & Guo, Curr. Opin. Neurobiol. 2007) to regulate mitochondrial function. Furthermore, pink1 and parkin promote mitochondrial fission and/or inhibit fusion (Deng et al, PNAS, 2008, in press) Overall, our studies underscore the importance of mitochondrial dysfunction as a central mechanism for PD pathogenesis. The identification of the pink1/parkin pathway with a mitochondria localized kinase (Pink1) and an E3 ubiquitin ligase (Parkin) opens the doors to the study of intra-mitochondrial signaling, nuclear-mitochondria signaling, and mitochondrial functions. Because Drosophila mutants for these genes show robust phenotypes, (while mutant mice do not), we are in a unique position to identify new components of this pathway and to dissect the molecular mechanisms that lead to mitochondrial dysfunction.

We are also interested in the mechanisms of cell death including apoptosis and autophagy, which are intimately related to the mechanisms of neurodegeneration (Annu. Rev. Cell Dev. Biol. 22:623; Nat. Rev. Genet. 5:911). In addition, we are also studying the developmental biology of these disease genes, since almost all of the genes mediating adult-onset neurodegeneration also impair development when mutated.

In summary, using Drosophila to dissect pathways leading to neurodegenerative disease is an exciting new area with many opportunities. We encourage you to explore it with us further.