Activation of the CaMKII-Sarm1-ASK1-p38 MAP Kinase Pathway Protects Against Axon Degeneration Caused by Loss of Mitochondria

Overview

Journal Elife

Specialty Biology

Date 2022 Mar 14

PMID 35285800

Authors

Chen Ding

Youjun Wu

Hadas Dabas

Marc Hammarlund

Affiliations

Soon will be listed here.

Abstract

Mitochondrial defects are tightly linked to axon degeneration, yet the underlying cellular mechanisms remain poorly understood. In PVQ axons that lack mitochondria degenerate spontaneously with age. Using an unbiased genetic screen, we found that cell-specific activation of CaMKII/UNC-43 suppresses axon degeneration due to loss of mitochondria. Unexpectedly, CaMKII/UNC-43 activates the conserved Sarm1/TIR-1-ASK1/NSY-1-p38 MAPK pathway and eventually the transcription factor CEBP-1 to protect against degeneration. In addition, we show that disrupting a trafficking complex composed of calsyntenin/CASY-1, Mint/LIN-10, and kinesin suppresses axon degeneration. Further analysis indicates that disruption of this trafficking complex activates the CaMKII-Sarm1-MAPK pathway through L-type voltage-gated calcium channels. Our findings identify CaMKII as a pivot point between mitochondrial defects and axon degeneration, describe how it is regulated, and uncover a surprising neuroprotective role for the Sarm1-p38 MAPK pathway in this context.

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References

Sporny M, Guez-Haddad J, Lebendiker M, Ulisse V, Volf A, Mim C . Structural Evidence for an Octameric Ring Arrangement of SARM1. J Mol Biol. 2019; 431(19):3591-3605. DOI: 10.1016/j.jmb.2019.06.030. View

Guo X, Zhou J, Starr C, Mohns E, Li Y, Chen E . Preservation of vision after CaMKII-mediated protection of retinal ganglion cells. Cell. 2021; 184(16):4299-4314.e12. PMC: 8530265. DOI: 10.1016/j.cell.2021.06.031. View

Catterall W . Voltage-gated calcium channels. Cold Spring Harb Perspect Biol. 2011; 3(8):a003947. PMC: 3140680. DOI: 10.1101/cshperspect.a003947. View

Araki Y, Tomita S, Yamaguchi H, Miyagi N, Sumioka A, Kirino Y . Novel cadherin-related membrane proteins, Alcadeins, enhance the X11-like protein-mediated stabilization of amyloid beta-protein precursor metabolism. J Biol Chem. 2003; 278(49):49448-58. DOI: 10.1074/jbc.M306024200. View

Ohno H, Kato S, Naito Y, Kunitomo H, Tomioka M, Iino Y . Role of synaptic phosphatidylinositol 3-kinase in a behavioral learning response in C. elegans. Science. 2014; 345(6194):313-7. DOI: 10.1126/science.1250709. View

Essuman K, Summers D, Sasaki Y, Mao X, DiAntonio A, Milbrandt J . The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017; 93(6):1334-1343.e5. PMC: 6284238. DOI: 10.1016/j.neuron.2017.02.022. View

Preuschhof C, Heekeren H, Li S, Sander T, Lindenberger U, Backman L . KIBRA and CLSTN2 polymorphisms exert interactive effects on human episodic memory. Neuropsychologia. 2009; 48(2):402-8. DOI: 10.1016/j.neuropsychologia.2009.09.031. View

Uchida Y, Gomi F . The role of calsyntenin-3 in dystrophic neurite formation in Alzheimer's disease brain. Geriatr Gerontol Int. 2016; 16 Suppl 1:43-50. DOI: 10.1111/ggi.12737. View

Yan D, Wu Z, Chisholm A, Jin Y . The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell. 2009; 138(5):1005-18. PMC: 2772821. DOI: 10.1016/j.cell.2009.06.023. View

10.

Osterloh J, Yang J, Rooney T, Fox A, Adalbert R, Powell E . dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012; 337(6093):481-4. PMC: 5225956. DOI: 10.1126/science.1223899. View

11.

Bezprozvanny I . Calcium signaling and neurodegenerative diseases. Trends Mol Med. 2009; 15(3):89-100. PMC: 3226745. DOI: 10.1016/j.molmed.2009.01.001. View

12.

Kristaponyte I, Hong Y, Lu H, Shieh B . Role of rhodopsin and arrestin phosphorylation in retinal degeneration of Drosophila. J Neurosci. 2012; 32(31):10758-66. PMC: 3430379. DOI: 10.1523/JNEUROSCI.0565-12.2012. View

13.

Loreto A, Hill C, Hewitt V, Orsomando G, Angeletti C, Gilley J . Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration. Neurobiol Dis. 2019; 134:104678. PMC: 7611775. DOI: 10.1016/j.nbd.2019.104678. View

14.

Sagasti A, HISAMOTO N, Hyodo J, Matsumoto K, Bargmann C . The CaMKII UNC-43 activates the MAPKKK NSY-1 to execute a lateral signaling decision required for asymmetric olfactory neuron fates. Cell. 2001; 105(2):221-32. DOI: 10.1016/s0092-8674(01)00313-0. View

15.

Takei N, Sobu Y, Kimura A, Urano S, Piao Y, Araki Y . Cytoplasmic fragment of Alcadein α generated by regulated intramembrane proteolysis enhances amyloid β-protein precursor (APP) transport into the late secretory pathway and facilitates APP cleavage. J Biol Chem. 2014; 290(2):987-95. PMC: 4294525. DOI: 10.1074/jbc.M114.599852. View

16.

Ding C, Hammarlund M . Aberrant information transfer interferes with functional axon regeneration. Elife. 2018; 7. PMC: 6231761. DOI: 10.7554/eLife.38829. View

17.

Horsefield S, Burdett H, Zhang X, Manik M, Shi Y, Chen J . NAD cleavage activity by animal and plant TIR domains in cell death pathways. Science. 2019; 365(6455):793-799. DOI: 10.1126/science.aax1911. View

18.

Frokjaer-Jensen C, Kindt K, Kerr R, Suzuki H, Melnik-Martinez K, Gerstbreih B . Effects of voltage-gated calcium channel subunit genes on calcium influx in cultured C. elegans mechanosensory neurons. J Neurobiol. 2006; 66(10):1125-39. DOI: 10.1002/neu.20261. View

19.

Shen K, Meyer T . Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. Science. 1999; 284(5411):162-6. DOI: 10.1126/science.284.5411.162. View

20.

Zalcman G, Federman N, Romano A . CaMKII Isoforms in Learning and Memory: Localization and Function. Front Mol Neurosci. 2018; 11:445. PMC: 6288437. DOI: 10.3389/fnmol.2018.00445. View