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Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury.
Exp Eye Res. 2018 06; 171:54-61.EE

Abstract

Optic neuropathies such as glaucoma are characterized by the degeneration of retinal ganglion cells (RGCs) and the irreversible loss of vision. In these diseases, focal axon injury triggers a propagating axon degeneration and, eventually, cell death. Previous work by us and others identified dual leucine zipper kinase (DLK) and JUN N-terminal kinase (JNK) as key mediators of somal cell death signaling in RGCs following axonal injury. Moreover, others have shown that activation of the DLK/JNK pathway contributes to distal axonal degeneration in some neuronal subtypes and that this activation is dependent on the adaptor protein, sterile alpha and TIR motif containing 1 (SARM1). Given that SARM1 acts upstream of DLK/JNK signaling in axon degeneration, we tested whether SARM1 plays a similar role in RGC somal apoptosis in response to optic nerve injury. Using the mouse optic nerve crush (ONC) model, our results show that SARM1 is critical for RGC axonal degeneration and that axons rescued by SARM1 deficiency are electrophysiologically active. Genetic deletion of SARM1 did not, however, prevent DLK/JNK pathway activation in RGC somas nor did it prevent or delay RGC cell death. These results highlight the importance of SARM1 in RGC axon degeneration and suggest that somal activation of the DLK/JNK pathway is activated by an as-yet-unidentified SARM1-independent signal.

Authors+Show Affiliations

Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY 14642, USA.Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Shiley Eye Institute, University of California, La Jolla, San Diego, CA 92037, USA.Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.Department of Neuroscience and Del Monte Institute for Neuroscience, University of Rochester Medical Center, Rochester, NY 14642, USA.Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Neuroscience, Department of Molecular Biology and Genetics, Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA; The Center for Visual Sciences, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: richard_libby@urmc.rochester.edu.Shiley Eye Institute, University of California, La Jolla, San Diego, CA 92037, USA. Electronic address: dwelsbie@ucsd.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29526794

Citation

Fernandes, Kimberly A., et al. "Role of SARM1 and DR6 in Retinal Ganglion Cell Axonal and Somal Degeneration Following Axonal Injury." Experimental Eye Research, vol. 171, 2018, pp. 54-61.
Fernandes KA, Mitchell KL, Patel A, et al. Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury. Exp Eye Res. 2018;171:54-61.
Fernandes, K. A., Mitchell, K. L., Patel, A., Marola, O. J., Shrager, P., Zack, D. J., Libby, R. T., & Welsbie, D. S. (2018). Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury. Experimental Eye Research, 171, 54-61. https://doi.org/10.1016/j.exer.2018.03.007
Fernandes KA, et al. Role of SARM1 and DR6 in Retinal Ganglion Cell Axonal and Somal Degeneration Following Axonal Injury. Exp Eye Res. 2018;171:54-61. PubMed PMID: 29526794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury. AU - Fernandes,Kimberly A, AU - Mitchell,Katherine L, AU - Patel,Amit, AU - Marola,Olivia J, AU - Shrager,Peter, AU - Zack,Donald J, AU - Libby,Richard T, AU - Welsbie,Derek S, Y1 - 2018/03/08/ PY - 2017/12/05/received PY - 2018/03/04/revised PY - 2018/03/07/accepted PY - 2018/3/13/pubmed PY - 2018/12/24/medline PY - 2018/3/13/entrez KW - Axon degeneration KW - Dual leucine zipper kinase (DLK) KW - Neurodegenerative disease KW - Retinal ganglion cell (RGC) KW - Sterile alpha and TIR motif containing 1 (SARM1) SP - 54 EP - 61 JF - Experimental eye research JO - Exp Eye Res VL - 171 N2 - Optic neuropathies such as glaucoma are characterized by the degeneration of retinal ganglion cells (RGCs) and the irreversible loss of vision. In these diseases, focal axon injury triggers a propagating axon degeneration and, eventually, cell death. Previous work by us and others identified dual leucine zipper kinase (DLK) and JUN N-terminal kinase (JNK) as key mediators of somal cell death signaling in RGCs following axonal injury. Moreover, others have shown that activation of the DLK/JNK pathway contributes to distal axonal degeneration in some neuronal subtypes and that this activation is dependent on the adaptor protein, sterile alpha and TIR motif containing 1 (SARM1). Given that SARM1 acts upstream of DLK/JNK signaling in axon degeneration, we tested whether SARM1 plays a similar role in RGC somal apoptosis in response to optic nerve injury. Using the mouse optic nerve crush (ONC) model, our results show that SARM1 is critical for RGC axonal degeneration and that axons rescued by SARM1 deficiency are electrophysiologically active. Genetic deletion of SARM1 did not, however, prevent DLK/JNK pathway activation in RGC somas nor did it prevent or delay RGC cell death. These results highlight the importance of SARM1 in RGC axon degeneration and suggest that somal activation of the DLK/JNK pathway is activated by an as-yet-unidentified SARM1-independent signal. SN - 1096-0007 UR - https://www.unboundmedicine.com/medline/citation/29526794/Role_of_SARM1_and_DR6_in_retinal_ganglion_cell_axonal_and_somal_degeneration_following_axonal_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4835(17)30844-8 DB - PRIME DP - Unbound Medicine ER -