Metabolic control of sensory neuron survival by the p75 neurotrophin receptor in Schwann cells

Abstract

We report that the neurotrophin receptor p75 contributes to sensory neuron survival during development through the regulation of cholesterol metabolism in Schwann cells. Selective deletion of p75 in Schwann cells resulted in a 30% loss of dorsal root ganglia (DRG) neurons and diminished thermal sensitivity, while knocking out p75 in neurons did not significantly alter their survival. P75 regulates Schwann cell cholesterol biosynthesis in response to BDNF, as reflected by activation of SREBP2, a master regulator of cholesterol synthesis. Schwann cells lacking p75 exhibited decreased activation of SREBP2 and a reduction in 7-dehydrocholesterol reductase (DHCR7) expression, resulting in accumulation of the neurotoxic intermediate, 7-dehyrocholesterol in the sciatic nerve. Restoration of DHCR7 in p75 null Schwann cells significantly attenuated DRG neuron loss. Together, these results reveal a mechanism by which the disruption of glial cell metabolism negatively influences sensory neuron survival, which has implications for a wide range of peripheral neuropathies.