Neuronal events and molecular pathways in active dendrite degeneration

DESCRIPTION (provided by applicant): Dendrites and axons extend long distances from the neuronal cell body and so can be damaged independently from it. It is known that axons possess their own active degeneration program that is controlled separately and is molecularly distinct from that of the cell body. It is not known whether dendrites possess a similar program. Dendrites are as important for normal neuronal function as axons, and exhibit morphological changes during seizures and stroke. We will therefore investigate the process of dendrite degeneration in a simple model system. Drosophila dendritic arborization neurons are sensory neurons under the larval cuticle that elaborate large dendritic trees similar in complexity to central neurons. We can identify the same individual cell in every animal, and can sever a single dendrite from this cell with a UV laser. We have preliminary evidence that this injury elicits an active degeneration program similar to axon degeneration after transection (Wallerian degeneration): distal dendrites are completely disassembled within 24 hours, and this disassembly is blocked by expression of the Wld(s), or Wallerian degeneration slow, protein. In this proposal, we outline a series of experiments to identify the major events that occur during dendrite degeneration and the molecular pathways that execute the degeneration program. We will use our expertise in live imaging and the basic cell biology of neurons to determine which subcellular systems are dismantled first: actin, microtubules or membrane trafficking. We will use available genetic tools to block known self-destruct machinery including caspases and the ubiquitin proteasome system to determine whether dendrites use the apoptotic or axonal degeneration program. We will also investigate whether candidate organelles, mitochondria and lysosomes, are important for dismantling dendrites. From our experiments overexpressing the Wld(s) protein, we know that it is possible to block the program of dendrite degeneration. We will therefore screen candidate genes and an overexpression library of transgenic Drosophila to identify additional ways to alter the course of dendrite degeneration. Using a simple model system to identify major cellular and molecular events during dendrite degeneration, and ways to change them, will rapidly advance our understanding of how neurons respond to environmental stresses including seizures and stroke. PUBLIC HEALTH RELEVANCE: Dendrites exhibit morphological signs of damage and degeneration under stresses including seizures and stroke. We will use a simple model system to investigate the cellular and molecular events that take place during dendrite degeneration, and will also identify proteins that can slow the degeneration program.