Emergence of the Wallerian degeneration pathway as a mechanism of secondary brain injury.

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Authors: Ciaran Hill and Andrea Loreto
Date: May 2021
From: Neural Regeneration Research(Vol. 16, Issue 5)
Publisher: Medknow Publications and Media Pvt. Ltd.
Document Type: Article
Length: 2,630 words
Lexile Measure: 1500L

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Byline: Ciaran. Hill, Andrea. Loreto

Augustus Volney Waller was a renowned British neurophysiologist who birthed the axon degeneration field in 1850 by describing curdling and fragmentation of the glossopharyngeal and hypoglossal cranial nerves of a frog following a transection injury. The degeneration of axons after a transection injury is now known as Wallerian degeneration (WD). Waller's work was expanded by Santiago Ramón y Cajal who described in detail the morphological stages of WD from monitory fragmentation of the axon and the granular disintegration of the neurofibrils to the final resorption of the axon. Interest in this field burgeoned in the early 1990's with the fortuitous discovery of a mutant mouse, known as the Wallerian degeneration Slow (WldS) mouse. Although overtly normal, its remarkable phenotype was discovered when the animals were subjected to a physical nerve injury and a profoundly slowed rate of axonal degeneration was revealed. This slow axon breakdown is intrinsic to neurons, present in central and peripheral nervous system axons, and associated with structural preservation and retention of the ability to conduct axon potentials for up to 2 weeks (a 10-fold delay).

The molecular mechanisms of WD began to be elucidated as the responsible gene (WldS) was mapped to mouse chromosome 4 using conventional linkage analysis. The WldS mutation was later revealed to involve a genomic rearrangement of two endogenous genes with splicing of resulting mRNAs to create an in-frame fusion protein. The C-terminal comprises the complete protein sequence of nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1), one of three NMNAT proteins, each with a specific subcellular localisation. The NMNAT proteins are a central component of the mammalian nicotinamide adenine dinucleotide (NAD) biosynthetic pathway. Studies on WldS revealed that the axonal isoform, NMNAT2, is an essential axon survival protein that is produced in the cell soma and continually shipped into the axon. Due to its rapid turnover rate, a transection injury, or other interruption of transport quickly deprives the distal axon of NMNAT2, causing axon degeneration. NMNAT2 is a labile protein and falling levels in the axon correlates with axon degeneration after a stereotypic latent period. WldS is capable of substituting for NMNAT2 in the axon and due to its longer half-life can preserve axonal integrity for a longer period (Coleman and Höke, 2020).

In 2012, a seminal paper was published that demonstrated the versatile power of Drosophila melanogaster and applied it to the axon degeneration field. A forward genetic screen of Drosophila , combined with rapid direct visualization of axon morphology, was used to identify novel genetic mutations that manifest with delayed WD. In contrast to the overexpression mutant WldS this screen identified loss-of-function mutations in the Drosophila gene sterile a/Armadillo/Toll-Interleukin receptor homology domain protein (dSarm). dSarm mutants have a remarkably robust axon protective phenotype that endured for the lifespan of the flies. Similarly, a murine knockout of the ortholog Sarm1 (sterile a and Toll/Interleukin 1 receptor motif containing protein 1) demonstrated robust protection against axotomy induced degeneration in cortical neurons and dorsal root ganglion neurons. In vivo...

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Gale Document Number: GALE|A642710643