Bax lies downstream of a mitogen-activated protein kinase (MAPK) pathway involving dual leucine-zipper kinase (DLK) and DLK’s direct targets MKK4/MKK7, which in turn activate c-Jun N-terminal kinase (JNK) ( Fernandes et al., 2012, 2014 Maes et al., 2017 Watkins et al., 2013 Welsbie et al., 2013, 2017).
Since those initial findings, more is now known about pathways that trigger somal Bax activation and how Wld S protects axons. This model emerged from findings that knockout (KO) of the proapoptotic protein Bax strongly protects RGC somas, but not distal axons after optic nerve crush (ONC), whereas the Wld S ( Wallerian degeneration slow) spontaneous mutation protects distal axons, but not RGC somas ( Howell et al., 2013 Li et al., 1999, 2000 Libby et al., 2005). Retinal ganglion cells (RGCs) are thought to undergo compartmentalized cell death after axonal injury, with different pathways controlling degeneration of the RGC soma and distal axons. 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. 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.
ZDHHC17-dependent palmitoylation enables DLK-dependent somal degeneration after ONC and also ensures NMNAT-dependent distal axon integrity in healthy optic nerves. Here, we report that palmitoylation of both DLK and NMNAT2 by the palmitoyl acyltransferase ZDHHC17 couples these signals. 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. After optic nerve crush (ONC), the cell bodies and distal axons of most retinal ganglion cells (RGCs) degenerate.
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