MAPping Death Pathways in Axons

Researchers have identified which enzymes axons use to trigger their own demise. Reporting in the January 15 Cell, first author Jing Yang and colleagues at Rockefeller University in New York found that mitogen-activated protein (MAP) kinases are essential for the disintegration of injured axons. Yang and senior author Marc Tessier-Lavigne believe the kinase cascade mobilizes proteases that tear down the cytoskeleton, though they still need to fill in a few gaps in the pathway. Scientists speculated that these kinases might also spring into action during neurodegenerative diseases, such as Alzheimer’s and amyotrophic lateral sclerosis.

Cascading kinases.

Axon damage initiates a MAP kinase pathway on the way to degeneration. [Image courtesy of Cell, Yang et al.]

Axon degeneration is a healthy process during the pruning of neurites in embryogenesis, or after injury, when a damaged axon must make way for new sprouts. The repair process, known as Wallerian degeneration, can be tempered by the Wlds mutation (Lunn et al., 1989; Nov 2001 news). Researchers have known for decades that there are multiple cellular programs to initiate axon degeneration, for example, an apoptotic-like pathway initiated by Death Receptor 6, which in turn is activated by an N-terminal fragment of APP (see Sep 2013 news; May 2014 news). In this study, the authors delineated a different Wallerian degeneration pathway, which does not involve the Wlds mutation.

They already knew the starting and ending points of the pathway. It starts with an adaptor protein called Sarm 1 (sterile alpha and Toll-interleukin-1 receptor motif containing 1), which Tessier-Lavigne described as the damage sensor. Other scientists discovered that deleting Sarm1 slowed down axon degeneration in fruit flies, and Yang confirmed that the same happens in mice (see Jun 2012 news). At the other end of the degeneration process, scientists have reported that ATP levels drop before the axon withers (Wang et al., 2005), and Yang confirmed this. Tessier-Lavigne suspects the ATP dip leads to a rise in intracellular calcium, activating the calpain enzymes that digest the cytoskeleton. (Yang et al., 2013; George et al., 1995).

What happens in the middle? Sarm1 often associates with MAP kinase pathways, so Yang inhibited or knocked down enzymes in this family in cultured sensory neurons from mice (Chuang et al., 2005; Kurz et al., 2007). Then, he squashed their axons. Most degenerated within a day, but a few hangers-on persisted, indicating they lacked genes for programmed degeneration. All told, Yang identified eight MAP family kinases that contributed to axon destruction (see image above). The authors propose that axon damage stimulates Sarm1, which activates MAP kinase signaling, leading to a drop in ATP, a rise in calcium, and calpain destruction of the axons. Now, the researchers are working on what happens between the MAP kinases and the ATP decline.

Yang studied acute trauma to disembodied neurons, but even so, the work may have implications for neurodegenerative disease, said Tessier-Lavigne. He pointed out that the Wlds mutation protects some mouse models of neurodegeneration, such as mice with a motor neuronopathy (Conforti et al., 2014; Wang et al., 2012).

“I suspect this is going to have relevance across many disease categories,” agreed Mark Albers of Massachusetts General Hospital in Charlestown, who was not involved in the study. He speculated that the same pathway that activates after dramatic nerve crush might also be active in axons subject to more minor insults, such as ischemia or the vascular disease that can precede Alzheimer’s. However, Albers cautioned that so far, Yang’s pathway has only been shown to be at work in sensory neurons.

Yang J, Wu Z, Renier N, Simon DJ, Uryu K, Park DS, Greer PA, Tournier C, Davis RJ, Tessier-Lavigne M. Pathological axonal death through a MAPK cascade that triggers a local energy deficit. Cell. 2015 Jan 15;160(1-2):161-76. [PubMed].

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