The Highwire Ubiquitin Ligase Promotes Axonal Degeneration by Tuning Levels of Nmnat Protein

• DOI: 10.1371/journal.pbio.1001440
• Publication Date: 2012-12-05T17:31:17Z
• Authors: Xin Xiong; Yan Hao; Kan Sun; Jiaxing Li; Xia Li; Bibhudatta Mishra; Pushpanjali Soppina; Chunlai Wu; Richard I. Hume; Catherine A. Collins
• Keywords: Wallerian degeneration; Degeneration (medical)

Axonal degeneration is a hallmark of many neuropathies, neurodegenerative diseases, and injuries. Here, using Drosophila injury model, we have identified highly conserved E3 ubiquitin ligase, Highwire (Hiw), as an important regulator axonal synaptic degeneration. Mutations in hiw strongly inhibit Wallerian multiple neuron types developmental stages. This new phenotype mediated by downstream target Hiw: the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenyltransferase (Nmnat), which acts parallel to previously known Hiw, Wallenda dileucine zipper kinase (Wnd/DLK) MAPKKK. Hiw promotes rapid disappearance Nmnat protein distal stump after injury. An increased level mutants both required sufficient Ectopically expressed mouse Nmnat2 also subject regulation axons synapses. These findings implicate role for endogenous its regulation, via mechanism, initiation Through independent Wnd/DLK, whose function proximal regenerate, plays central coordinating regenerative degenerative responses