Neurodegeneration and Aging: Insight from Drosophila. Nancy M. Bonini. Dept Biol, 306 Leidy Labs, Univ Pennsylvania/HHMI, Philadelphia, PA.

   Human neurodegenerative diseases, like Huntingtons disease and the spinocerebellar ataxias, are late-onset progressive neurodegenerative disorders for which few cures or treatments are available. To develop new approaches, the Bonini laboratory has been using the fly to provide insight that we then extend to the human disease. We use the human disease gene to recreate the disease toxicity in the fly, and then take advantage of powerful molecular genetic approaches in the fly to define pathways and mechanisms. These studies have revealed multiple pathways involved in neurodegeneration, including toxicities due to RNA pathways. These processes include toxic activities of the mRNA encoding the disease proteins for repeat expansion diseases, RNA binding proteins and their altered activities, and modulation by miRNAs, including novel aspects of miRNA regulation such as 3'end trimming by the exonuclease Nibbler. A key miRNA we identified that links age-associated processes with long-term brain integrity in Drosophila is miR-34. We have extended our studies from longterm integrity of the brain to acute neural injury, with the development of a novel adult-stage injury model of the fly wing. Taken together, our approaches and findings highlight the conservation of pathways with humans, and ways to use Drosophila in order to define critical new pathways that impact integrity of the nervous system.