Abstract
Axon degeneration sculpts neuronal connectivity patterns during development and is an early hallmark of several adult-onset neurodegenerative disorders. Substantial progress has been made in identifying effector mechanisms driving axon fragmentation, but less is known about the upstream signaling pathways that initiate this process. Here, we investigate the behavior of the actin-spectrin-based Membrane-associated Periodic Skeleton (MPS), and effects of actin and spectrin manipulations in sensory axon degeneration. We show that trophic deprivation (TD) of mouse sensory neurons causes a rapid disassembly of the axonal MPS, which occurs prior to protein loss and independently of caspase activation. Actin destabilization initiates TD-related retrograde signaling needed for degeneration; actin stabilization prevents MPS disassembly and retrograde signaling during TD. Depletion of βII-spectrin, a key component of the MPS, suppresses retrograde signaling and protects axons against degeneration. These data demonstrate structural plasticity of the MPS and suggest its potential role in early steps of axon degeneration.
Highlights
Neurons and their axons are produced in excess during mammalian development, followed by a wide-spread culling of excess axons or axonal branches as the nervous system matures
We found that trophic deprivation (TD) induced a rapid disassembly of the Membrane-associated Periodic Skeleton (MPS), an observation reported independently (Unsain et al, 2018) while our paper was in preparation
To examine the effect of Jasp treatment on TD-induced retrograde signaling in axon degeneration, we examined phosphorylation of c-Jun and found that application of Jasp prevented the TD-induced rise in phosphorylated c-Jun (p-c-Jun) (Figure 4C,D), which is required in part for TD-induced degeneration (Simon et al, 2016)
Summary
Neurons and their axons are produced in excess during mammalian development, followed by a wide-spread culling of excess axons or axonal branches as the nervous system matures This is exemplified in the development of the peripheral nervous system where sensory axons of the dorsal root ganglion (DRG) compete for limited quantities of target-derived neurotrophins that promote axon survival. A major unanswered question is to define the early signals that induce retrograde signaling to initiate axon degeneration. These upstream pathways represent attractive therapeutic targets to mitigate pathological axon degeneration (Chao and Lee, 2004; Le Pichon et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
