# A role for the p75 neurotrophin receptor in Schwann cell regulation of sensory neurons

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $509,058

## Abstract

Peripheral neuropathy is a debilitating and often painful condition associated with a wide variety of
diseases. Unfortunately, in most cases, there is no treatment for the neurodegeneration, highlighting the need
to better understand the mechanisms regulating axon integrity and neuron viability. One key regulator of
neuron survival and axon growth is the family of neurotrophins, which act through binding to the Trk family of
receptor tyrosine kinases and the p75 neurotrophin receptor. Activation of the Trks promotes survival and
growth, while stimulation of p75 can induce apoptosis and axon degeneration. However, p75 can also form a
high affinity complex with the Trks that mediates pro-survival signaling. Reduced neurotrophin signaling in
neurons leads to impaired sensory function in humans and complete loss of neurotrophin signaling leads to
extensive neuronal apoptosis. For example, mice lacking p75 lose ~50% of the sensory neurons in their dorsal
root ganglia (DRG), which was presumed to be due to a reduction in the p75-Trk complex in the neurons,
leading to inadequate trophic support. However, p75 is also expressed in Schwann cells and we made the
surprising discovery that selective deletion of p75 in Schwann cells resulted in a 30% reduction in DRG
neurons and decreased heat sensitivity. These results support growing evidence that glial cells are critical
modulators of neuronal function and viability. We also found altered lipid metabolism in p75-/- nerves, with a
marked increase in oxysterols and acylcarnitines, which are neurotoxic. Therefore, we hypothesize that p75
null Schwann cells release these lipids, leading to neurodegeneration. In considering how p75 could regulate
lipid metabolism, we identified a novel complex between p75 and the receptor tyrosine kinase ErbB2 via the
polarity protein, Par3, in Schwann cells. Binding of the neurotrophin BDNF to this complex activated ErbB2
signaling and in nerves from p75 deficient mice there was a reduction in ErbB2 activity. During normal
development, signaling from receptor tyrosine kinases in Schwann cells activates lipid biogenesis and shuts
down -oxidation to produce myelin. We propose that loss of the p75/ErbB2/Par3 complex disrupts cholesterol
biosynthesis, leading to oxysterol production, and shifts lipids to -oxidation, which results in accumulation of
acylcarnitines. We further hypothesize that the release of oxysterols and acylcarnitines by the Schwann cells
causes degeneration of sensory neurons. In this project, we will test these hypotheses by a) defining the
populations of neurons affected in mice lacking p75 in Schwann cells; b) determining whether the production of
oxysterols and/or acylcarnitines by the glia accounts for the neuron loss; c) elucidating the mechanisms by
which p75 regulates lipid metabolism. The results will reveal unique mechanisms by which Schwann cells
modulate neuron viability, thereby providing new insights into the etiology of peripheral neuropathy.

## Key facts

- **NIH application ID:** 9934301
- **Project number:** 5R01NS107456-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Bruce D Carter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,058
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934301

## Citation

> US National Institutes of Health, RePORTER application 9934301, A role for the p75 neurotrophin receptor in Schwann cell regulation of sensory neurons (5R01NS107456-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934301. Licensed CC0.

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