A Model of Toxic Neuropathy inDrosophilaReveals a Role for MORN4 in Promoting Axonal Degeneration

• DOI: 10.1523/jneurosci.4951-11.2012
• Publication Date: 2012-04-11T16:29:13Z
• Authors: Martha R. C. Bhat...; Josiah Gerdts; Sarah A. Naylor; Emily X. Royse; Sarah Y. Ebstein; Yo Sasaki; Jeffrey Milbrandt; Aaron DiAntonio
• Keywords: Axotomy; Degeneration (medical); Axonal Degeneration; Axoplasmic transport; Wallerian degeneration

Axonal degeneration is a molecular self-destruction cascade initiated following traumatic, toxic, and metabolic insults. Its mechanism underlies number of disorders including hereditary diabetic neuropathies the neurotoxic side effects chemotherapy drugs. Molecules that promote axonal could represent potential targets for therapy. To identify such molecules, we designed screening platform based on intoxication Drosophila larvae with paclitaxel (taxol), chemotherapeutic agent causes neuropathy in cancer patients. In , taxol treatment swelling, fragmentation, loss axons larval peripheral nerves. This not due to apoptosis neurons. Taxol-induced shares execution mechanisms vertebrates, inhibition by both NMNAT (nicotinamide mononucleotide adenylyltransferase) expression wallenda /DLK (dual leucine zipper kinase). pilot RNAi-based screen found knockdown retinophilin ( rtp ), which encodes MORN (membrane occupation recognition nexus) repeat-containing protein, protects from presence taxol. Loss-of-function mutants replicate this protection. Knockdown also delays severed olfactory axons. We demonstrate mouse ortholog MORN4, promotes sensory axotomy, illustrating conservation function. Hence, new model can evolutionarily conserved genes degeneration, so candidate therapeutic wide-range axonopathies.