Discovery of SAD, a novel gene required for axonal integrity in ageing, by an unbiased genetic screen using the Drosophila wing as a model. Yanshan Fang, Xiuyin Teng, Yongqing Zhu, Nancy Bonini. HHMI, Dept. of Biology, Univ. of Pennsylvania, Philadelphia, PA 19104.

   Axon degeneration is a prominent feature of spinal cord injury and neurodegenerative diseases. Studies of the Wld^S mouse indicate that axon degeneration is an active process, however, the underlying mechanisms remain elusive. To identify novel components controlling axonal integrity, it is desirable to perform unbiased, large-scale screening.
   Drosophila is an exceptional model system for the study of human diseases. We thus developed a model of nerve injury using the Drosophila wing, which is translucent, allowing us to highlight the axons using fluorescent proteins and to monitor axonal changes in response to traumatic injury and ageing in live flies. Using this model, we conducted a genetic screen in a Wld^S-sensitized background.
   Among the initial candidates, we found a novel mutant of a functionally unknown gene. This mutant not only diminishes Wld^S protection, but also displays striking age-dependent spontaneous axon degeneration on its own. For this phenotype, we named it: Spontaneous Axon Degeneration (SAD). Further examination reveals massive vacuoles in the brain of aged SAD flies, a hallmark of progressive neurodegeneration in the CNS. Moreover, the lifespan of the SAD mutant is significantly shortened. In addition, aged SAD flies have elevated sensitivity to heat and physical stress, although their climbing capability is normal.
   We are defining the nature and function of SAD. Protein feature analysis suggests that SAD is involved in chromatin remodeling. Ongoing experiments include generating SAD transgenic flies to confirm its neural effects and making anti-SAD antibody to define its expression patterns. By such study, we hope to reveal the molecular mechanism of SAD in age-associated maintenance of the nervous system, which will provide important foundation for new therapeutic targets of neurodegeneration.