Axon pathology and loss in some neurodegenerative disorders involve mechanisms that are related to those occurring during Wallerian degeneration after axon injury. Many aspects of the process of Wallerian degeneration appear to be highly conserved and have been studied in Drosophila and other model organisms.
Levels and localization of NMNAT proteins (Nmnat in Drosophila; NMNAT1, NMNAT2, and NMNAT3 in human) are crucial for the execution of axon death signaling. The first discovery of a mutation which attenuates axon death irrespective of NMNAT levels was made in Drosophila: through an unbiased forward-genetic screen for axon death defective mutants, several loss-of-function alleles of the gene 'Drosophila sterile alpha and armadillo motif' (Sarm) were isolated; the orthologous human gene is SARM1. These genes play roles in NAD(+) metabolism.
For an RNAi-effected loss-of-function phenotype of Dmel\Nmnat, heterologous rescue (functional complementation) has been demonstrated using the mouse genes Mmus\Nmnat1 and Mmus\Nmnat3.
The roles of additional genes involved in injury-induced axon degeneration have been investigated in Drosophila. The E3 ubiquitin ligase highwire (hiw) regulates the turnover of Nmnat; the ortholgous human gene is MYCBP2. hiw also plays a role in regulation of Dmel\wnd, which becomes activated in neurons after axotomy; wnd is orthologous to human MAP3K13 and MAP3K12. Similar to hiw mutants, mutations in Dmel\axed attenuate axon death signaling for the lifespan of the fly; however, the precise mechanistic function of axed is currently unknown. There are 4 orthologs of axed in human, BTBD1, BTBD2, BTBD3, BTBD6. The fly gene Dmel\Vps4, an ESCRT (endosomal sorting complex) component, has also been identified as having a role in axonal integrity and injury-induced degeneration.
Role of mitochondria in this process has been investigated in flies, supporting a mitochondria-independent mechanism. Although mitochondrial dysfunction may trigger axon degeneration, mitochondria do not appear to be necessary for the process.
The mouse gene Mmus\Wld has been introduced into flies and has been characterized in relation to this disease model. Wld is a fusion gene formed from Ube4b and Nmnat1 as part of a triplication; the neural degeneration of injured axons is delayed in animals with this genotype. Also designated Wld[S], it has been used extensively in the study of Wallerian degeneration in mouse.
[updated Mar. 2024 by FlyBase; FBrf0222196]
Axon degeneration is a prominent early feature of most neurodegenerative disorders and can also be induced directly by nerve injury in a process known as Wallerian degeneration (Conforti, et al., 2014; pubmed:24840802).
Axon death signaling is activated when the axon is cut, crushed or stretched; it also appears to be a major contributor in different animal models of neurological conditions, e.g. where axons degenerate in the absence of injury (Rosell and Neukomm, 2019; pubmed:31455157).
Identified by and named after Augustus Waller, Wallerian degeneration (WD) is an umbrella term under which two distinct mechanisms occur: first, severed axons, separated from the soma, actively execute their own disassembly (axon death) within 1 day, through an evolutionary conserved axon death signaling cascade; and second, surrounding glial cells engage and clear the resulting debris within 3-5 days; axon death and glial clearance are separate processes (Rosell and Neukomm, 2019; pubmed:31455157).
NMNAT1 encodes a protein that catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP; specifically localized to the cell nucleus. [Gene Cards, NMNAT1; 2022.03.16]
SARM1 encodes a NAD(+) hydrolase that plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism. [Gene Cards, SARM1; 2022.03.16]
MYCBP2 encodes an E3 ubiquitin-protein ligase. [Gene Cards, MYCBP2; 2022.03.16]
High-scoring ortholog of human VPS4A and VPS4B ((1 Drosophila to 2 human).
High-scoring ortholog of human NMNAT1 and NMNAT3; moderate-scoring ortholog of human NMNAT2 (1 Drosophila to 3 human).
High-scoring ortholog of human SARM1 (1 Drosophila to 1 human).
Low-scoring ortholog of several human genes encoding BTB-domain-containing proteins, including BTBD3, BTBD6, BTBD1, and BTBD2.
High-scoring ortholog of human MYCBP2 (1 Drosophila to 1 human).
Moderate-scoring ortholog of human MAP3K13 and MAP3K12 (1 Drosophila to 2 human).
