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

doi:10.1016/j.celrep.2020.108365

Coupled Control of Distal Axon Integrity and Somal Responses to Axonal Damage by the Palmitoyl Acyltransferase ZDHHC17

Cell Rep. 2020 Nov 17;33(7):108365. doi: 10.1016/j.celrep.2020.108365.

Authors

Affiliations

¹ Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
² Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
³ Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
⁴ Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
⁵ 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.
⁶ 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. Electronic address: gareth.thomas@temple.edu.

Abstract

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.

Keywords: DHHC; JNK; MAPK; SARM1; Wallerian; Wlds.

Publication types

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

MeSH terms

Acyltransferases / metabolism*
Acyltransferases / physiology
Animals
Axons / metabolism*
Axons / physiology
Caenorhabditis elegans
Cell Survival / physiology
Cells, Cultured
Disease Models, Animal
Ganglia, Spinal / metabolism
HEK293 Cells
Humans
Lipoylation
MAP Kinase Kinase Kinases / metabolism
Mice
Mice, Inbred C57BL
Nerve Degeneration / pathology
Nicotinamide-Nucleotide Adenylyltransferase / metabolism
Optic Nerve / metabolism
Rats
Rats, Sprague-Dawley
Retinal Ganglion Cells / metabolism*
Retinal Ganglion Cells / physiology

Substances

Acyltransferases
MAP Kinase Kinase Kinases
mitogen-activated protein kinase kinase kinase 12
Nicotinamide-Nucleotide Adenylyltransferase
Nmnat2 protein, mouse
Zdhhc17 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding