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.—Amber Dance

Comments

  1. Despite the identification of several molecular players, our knowledge of the mechanisms at work in axon degeneration has been fragmented. With a systematic analysis, this study demonstrated that many of these molecules are, in fact, functionally connected, revealing a signaling pathway that mediates the initiation of the degenerative processes. These findings should stimulate further studies to examine whether axon degeneration in different disease conditions shares all or part of the pathway. Such information will be important for designing relevant axon protective strategies.

    View all comments by Zhigang He

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References

News Citations

  1. Protein Chimera Found to Protect Axons from Degeneration
  2. Cellular Pruning Shears Reshape Connections in Adults
  3. Reports Weaken Death Receptor Link to Alzheimer's Disease
  4. Staying Alive: Freed of a Single Gene, Severed Axons Defy Death

Paper Citations

  1. Lunn ER, Perry VH, Brown MC, Rosen H, Gordon S. Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve. Eur J Neurosci. 1989;1(1):27-33. PubMed.
  2. Wang J, Zhai Q, Chen Y, Lin E, Gu W, McBurney MW, He Z. A local mechanism mediates NAD-dependent protection of axon degeneration. J Cell Biol. 2005 Aug 1;170(3):349-55. PubMed.
  3. Yang J, Weimer RM, Kallop D, Olsen O, Wu Z, Renier N, Uryu K, Tessier-Lavigne M. Regulation of axon degeneration after injury and in development by the endogenous calpain inhibitor calpastatin. Neuron. 2013 Dec 4;80(5):1175-89. Epub 2013 Nov 7 PubMed.
  4. George EB, Glass JD, Griffin JW. Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels. J Neurosci. 1995 Oct;15(10):6445-52. PubMed.
  5. Chuang CF, Bargmann CI. A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes Dev. 2005 Jan 15;19(2):270-81. PubMed.
  6. Kurz CL, Shapira M, Chen K, Baillie DL, Tan MW. Caenorhabditis elegans pgp-5 is involved in resistance to bacterial infection and heavy metal and its regulation requires TIR-1 and a p38 map kinase cascade. Biochem Biophys Res Commun. 2007 Nov 16;363(2):438-43. Epub 2007 Sep 12 PubMed.
  7. Conforti L, Gilley J, Coleman MP. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci. 2014 Jun;15(6):394-409. PubMed.
  8. Wang JT, Medress ZA, Barres BA. Axon degeneration: molecular mechanisms of a self-destruction pathway. J Cell Biol. 2012 Jan 9;196(1):7-18. PubMed.

Further Reading

Papers

  1. Blum ES, Abraham MC, Yoshimura S, Lu Y, Shaham S. Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science. 2012 Feb 24;335(6071):970-3. PubMed.
  2. Chen CY, Lin CW, Chang CY, Jiang ST, Hsueh YP. Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. J Cell Biol. 2011 May 16;193(4):769-84. PubMed.
  3. Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J. Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci. 2013 Aug 14;33(33):13569-80. PubMed.
  4. Wang J, Zhai Q, Chen Y, Lin E, Gu W, McBurney MW, He Z. A local mechanism mediates NAD-dependent protection of axon degeneration. J Cell Biol. 2005 Aug 1;170(3):349-55. PubMed.
  5. Couillault C, Pujol N, Reboul J, Sabatier L, Guichou JF, Kohara Y, Ewbank JJ. TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat Immunol. 2004 May;5(5):488-94. Epub 2004 Mar 28 PubMed.
  6. Chen M, Maloney JA, Kallop DY, Atwal JK, Tam SJ, Baer K, Kissel H, Kaminker JS, Lewcock JW, Weimer RM, Watts RJ. Spatially coordinated kinase signaling regulates local axon degeneration. J Neurosci. 2012 Sep 26;32(39):13439-53. PubMed.
  7. Xiong X, Collins CA. A conditioning lesion protects axons from degeneration via the Wallenda/DLK MAP kinase signaling cascade. J Neurosci. 2012 Jan 11;32(2):610-5. PubMed.
  8. Conforti L, Gilley J, Coleman MP. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci. 2014 Jun;15(6):394-409. PubMed.

Primary Papers

  1. 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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