Wednesday, October 9, 2024
10/9/2024
Summary: Axon degeneration occurs during development of the nervous system as well as neuropathologies including Alzheimer's, Luo Gehrig's, and Huntington's disease as well as stroke, and spinal cord injury. A common but poorly defined feature of all forms of neural degeneration is the emergence of swellings or spheroids that appear prior to irreversible breakdown of the axon. These degenerative spheroids were first observed in the early 1900's by Cajal but their function has gone undescribed until our recent work. We found that in both developmental and pathological contexts, diverse degenerative triggers converge on spheroid formation. In both contexts, spheroids grow to the point of rupture and their contents hasten irreversible axon breakdown in an autocrine and paracrine manner. This suggests that spheroids are not merely a morphological hallmark of degenerating axons but also perform a critical function that may be universal to all forms of axon degeneration. We also suggest that spheroid formation and rupture demarcates the transition from latent to catastrophic phases of axon degeneration. In Aim 1, we characterize the properties of spheroid formation (e.g. growth, movement, fusion, and rupture) as well as the signaling pathways that control spheroid formation. In Aim2, we examine the pathways downstream of spheroid rupture in regulating catastrophic axon degeneration. Finally, in Aim3, we determine whether mouse lines with impaired Wallerian degeneration but intact (DR6-/- and Sarm1-/-) or deficient (Wlds) spheroid formation influences recruitment of macrophages and regenerative capacity. Understanding how spheroids are formed and how their contents induce catastrophic axon breakdown represents an important avenue toward developing therapeutics for nervous system degeneration. Our expertise in mouse genetics, developmental neuroscience, cytokine signaling, and biochemical analysis places us in a unique position to delineate mechanisms that have eluded the field for decades.
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