Coupled Control of Distal Axon Integrity and Somal Responses to Axonal Damage by the Palmitoyl Acyltransferase ZDHHC17
Jingwen Niu,
Shaun S. Sanders,
Hey-Kyeong Jeong,
Sabrina M. Holland,
Yue Sun,
Kaitlin M. Collura,
Luiselys M. Hernandez,
Haoliang Huang,
Michael R. Hayden,
George M. Smith,
Yang Hu,
Yishi Jin,
Gareth M. Thomas
Affiliations
Jingwen Niu
Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
Shaun S. Sanders
Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
Hey-Kyeong Jeong
Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
Sabrina M. Holland
Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
Yue Sun
Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
Kaitlin M. Collura
Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
Luiselys M. Hernandez
Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
Haoliang Huang
Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
Michael R. Hayden
Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada
George M. Smith
Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA; Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Yang Hu
Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
Yishi Jin
Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
Gareth M. Thomas
Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Corresponding author
Summary: After optic nerve crush (ONC), the cell bodies and distal axons of most retinal ganglion cells (RGCs) degenerate. RGC somal and distal axon degenerations were previously thought to be controlled by two parallel pathways, involving activation of the kinase dual leucine-zipper kinase (DLK) and loss of the axon survival factor nicotinamide mononucleotide adenylyltransferase-2 (NMNAT2), respectively. Here, we report that palmitoylation of both DLK and NMNAT2 by the palmitoyl acyltransferase ZDHHC17 couples these signals. ZDHHC17-dependent palmitoylation enables DLK-dependent somal degeneration after ONC and also ensures NMNAT-dependent distal axon integrity in healthy optic nerves. We provide evidence that ZDHHC17 also controls survival-versus-degeneration decisions in dorsal root ganglion (DRG) neurons, and we identify conserved motifs in NMNAT2 and DLK that govern their ZDHHC17-dependent regulation. These findings suggest that the control of somal and distal axon integrity should be considered as a single, holistic process, mediated by the concerted action of two palmitoylation-dependent pathways.
