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 6

Fabry Schwann cells release the protein p11 (S100A10), which alters isolated DRG neuron function and induces pain-like behaviors in rats.

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Fabry Schwann cells release the protein p11 (S100A10), which alters isol...
(A) NanoLC-MS/MS analysis was performed on Fabry- and WT-SCM. Fabry-SCM contained significantly more p11 (S100-A10) compared with WT samples; refer to Supplemental Table 4 for a list of the other significantly altered proteins. (B) Representative immunofluorescence images of DRG neuron soma incubated with 100 ng/mL of His-tagged recombinant p11 or without p11 (CTRL) (scale bar = 20 μm). (C) Representative calcium imaging traces of 0 ng/mL and 100 ng/mL p11 incubated neurons exposed to 20 mM KCl for 10 seconds, 50 mM KCl used as a positive control. Traces are representative from 3 animals. (D) Significantly more neurons incubated with soluble p11 at various concentrations (0.5–1,000 ng/mL) responded to mild depolarization with 20 mM KCl as assessed using calcium imaging. (E) Neurons incubated with soluble p11 exhibited increased 20 mM KCl–induced calcium influx. (F) Intraplantar injection of p11 into naive Sprague-Dawley rats decreased hind paw withdrawal thresholds to von Frey stimulation. (A) n = SCM samples from 5 animals per genotype, plotted per animal; (B) representative images, 4 independent DRG cultures; (C–E) n = 140–160 neurons per treatment from 3 animals; (F) n = 8 animals per dose. (A, E, and F) reported as mean ± SEM, (D) reported as mean. (A) Benjamini-Hochberg–corrected 2-tailed Student’s t test, (C) χ2 with corrected Fisher’s exact post hoc comparison, (E) 1-way ANOVA with Bonferroni post hoc comparison, (F) 2-way repeated measures ANOVA with Bonferroni post hoc comparison. * P < 0.05, ** P < 0.01, *** P < 0.001. BL, preinjection baseline behavioral measurements; SCM, Schwann cell–conditioned media.