Pebbled makes ripples: A transcription factor primes glutamatergic but not cholinergic neurons for degeneration

Abstract

Neurons can extend axons that cover long distances, from several microns and up to 1 m in adult humans. Axon degeneration is a hallmark of several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, and many more (1). Understanding the mechanisms maintaining axon integrity—and thus neuronal function—is a major question during development, as well as during disease and long life. When axons are detached from the cell body, due to injury or neuropathy, the distal part undergoes fragmentation and debris begin to be cleared within 1.5 d by phagocytes in a process termed Wallerian degeneration (WD) (2). For many years it was thought that WD was a passive process caused by a failure of the severed axon to receive nutrients and energy required for maintenance from the cell soma. The discovery of the spontaneously arising Wallerian degeneration slow (Wlds) mouse changed this viewpoint. In these Wlds mice, the severed axon can survive up to several weeks, suggesting that WD is an active rather than passive cellular process (3). The Wlds mutation results in the presence of a chimeric protein made up of a small part of the E4 ubiquitin ligase, Ube4b, fused to the full-length Nmnat1, a component of NAD+ biosynthesis (4). The mechanism by which Wlds provides protection against degeneration of both central and peripheral axons has not yet been fully elucidated but is probably dependent upon high Nmnat activity (5). This finding that protein function could delay axon death led several groups to search for both axon death and axon protective genes in an attempt to further understand axon maintenance. A forward genetic screen in Drosophila searching for suppressors of WD identified an additional key modulator: the Drosophila sterile α/Armadillo/Toll-Interleukin receptor homology domain (dsarm) that functions in a Wlds … [↵][1]1To whom correspondence should be addressed. Email: oren.schuldiner{at}weizmann.ac.il. [1]: #xref-corresp-1-1