Abstract
We report that the neurotrophin receptor p75 contributes to sensory neuron survival through the regulation of cholesterol metabolism in Schwann cells. Selective deletion of p75 in mouse Schwann cells of either sex resulted in a 30% loss of dorsal root ganglia (DRG) neurons and diminished thermal sensitivity. P75 regulates Schwann cell cholesterol biosynthesis in response to BDNF, forming a co-receptor complex with ErbB2 and activating ErbB2-mediated stimulation of sterol regulatory element binding protein 2 (SREBP2), a master regulator of cholesterol synthesis. Schwann cells lacking p75 exhibited decreased activation of SREBP2 and a reduction in 7-dehydrocholesterol (7-DHC) reductase (DHCR7) expression, resulting in accumulation of the neurotoxic intermediate, 7-dehyrocholesterol in the sciatic nerve. Restoration of DHCR7 in p75 null Schwann cells in mice significantly attenuated DRG neuron loss. Together, these results reveal a mechanism by which the disruption of lipid metabolism in glial cells negatively influences sensory neuron survival, which has implications for a wide range of peripheral neuropathies.
Original language | English (US) |
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Pages (from-to) | 8710-8724 |
Number of pages | 15 |
Journal | Journal of Neuroscience |
Volume | 41 |
Issue number | 42 |
DOIs | |
State | Published - Oct 20 2021 |
Externally published | Yes |
Keywords
- Cholesterol
- Metabolism
- Neurotoxicity
- P75
- Schwann cells
- Sensory neurons
ASJC Scopus subject areas
- General Neuroscience