Fabry disease Schwann cells release p11 to induce sensory neuron hyperactivity
Tyler B. Waltz, Dongman Chao, Eve K. Prodoehl, Jonathan D. Enders, Vanessa L. Ehlers, Bhavya S. Dharanikota, Nancy M. Dahms, Elena Isaeva, Quinn H. Hogan, Bin Pan, Cheryl L. Stucky
Tyler B. Waltz, Dongman Chao, Eve K. Prodoehl, Jonathan D. Enders, Vanessa L. Ehlers, Bhavya S. Dharanikota, Nancy M. Dahms, Elena Isaeva, Quinn H. Hogan, Bin Pan, Cheryl L. Stucky
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Research Article Neuroscience

Fabry disease Schwann cells release p11 to induce sensory neuron hyperactivity

Abstract

Patients with Fabry disease suffer from chronic debilitating pain and peripheral sensory neuropathy with minimal treatment options, but the cellular drivers of this pain are unknown. Here, we propose a mechanism we believe to be novel in which altered signaling between Schwann cells and sensory neurons underlies the peripheral sensory nerve dysfunction we observed in a genetic rat model of Fabry disease. Using in vivo and in vitro electrophysiological recordings, we demonstrated that Fabry rat sensory neurons exhibited pronounced hyperexcitability. Schwann cells probably contributed to this finding because application of mediators released from cultured Fabry Schwann cells induced spontaneous activity and hyperexcitability in naive sensory neurons. We examined putative algogenic mediators using proteomic analysis and found that Fabry Schwann cells released elevated levels of the protein p11 (S100A10), which induced sensory neuron hyperexcitability. Removal of p11 from Fabry Schwann cell media caused hyperpolarization of neuronal resting membrane potentials, indicating that p11 may contribute to the excessive neuronal excitability caused by Fabry Schwann cells. These findings demonstrate that sensory neurons from rats with Fabry disease exhibit hyperactivity caused in part by Schwann cell release of the protein p11.

Authors

Tyler B. Waltz, Dongman Chao, Eve K. Prodoehl, Jonathan D. Enders, Vanessa L. Ehlers, Bhavya S. Dharanikota, Nancy M. Dahms, Elena Isaeva, Quinn H. Hogan, Bin Pan, Cheryl L. Stucky

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Figure 7

p11 contributes to the resting membrane depolarization of naive DRG neurons treated with Fabry-SCM.

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p11 contributes to the resting membrane depolarization of naive DRG neur...
(A) Naive neurons exposed to 100 ng/mL p11 exhibited significantly depolarized RMPs. (B) Incubation of p11 reduced rheobase in naive neurons. (C) Current protocol and representative traces of neurons undergoing current stimulation of 200 pA above rheobase for 500 ms. (D) Neurons exposed to p11 exhibit increased firing frequency to suprathreshold current stimulation compared with CTRL. (E and F) Incubation with 100 ng/mL p11 enhanced peak sodium current densities. (G) The maximum inward current density was higher in neurons exposed to p11, reported as absolute values. Mean capacitance values (pF ± SEM) for neurons tested were 25.5 ± 2.0 and 23.5 ± 1.9 for CTRL and p11-incubated neurons, respectively. (H) p11 immunodepletion protocol from Fabry-SCM media for electrophysiology studies in naive DRG neurons. (I) Immunodepletion reduced p11 concentration of Fabry-SCM by 86%, with WT-SCM exhibiting concentrations below the limit of detection as measured by ELISA. (J) Naive neurons exposed to Fabry-SCM-ID exhibited a hyperpolarized RMP compared with neurons treated with Fabry-SCM. Values reported as mean ± SEM. (A–D) n = 28 neurons per treatment from 7 animals; (E–G) n = 26 neurons per treatment from 8 animals; (I) n = 5 WT and Fabry Schwann cell cultures from individual animals; (J) n = 31 neurons per treatment from 8 animals. (A, B, G, and J) Unpaired Student’s t test, (D and F) 2-way repeated measures ANOVA with main effect of treatment, (I) 2-way ANOVA, Bonferroni post hoc comparison. * P < 0.05, ** P < 0.01. SCM, Schwann cell–conditioned media; SCM-ID, Schwann cell–conditioned media with immunodepleted p11; AP, action potential.