# Extrinsic Mechanisms Governing Injury-Induced Axon Degeneration

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $468,481

## Abstract

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.

## Key facts

- **NIH application ID:** 10211546
- **Project number:** 2R01NS091617-06
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Christopher D Deppmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $468,481
- **Award type:** 2
- **Project period:** 2015-08-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211546

## Citation

> US National Institutes of Health, RePORTER application 10211546, Extrinsic Mechanisms Governing Injury-Induced Axon Degeneration (2R01NS091617-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10211546. Licensed CC0.

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