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
View: Text | PDF
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

×

Figure 4

Fabry Schwann cell mediators induce peripheral neuron sensitization.

Options: View larger image (or click on image) Download as PowerPoint
Fabry Schwann cell mediators induce peripheral neuron sensitization. (A)...
(A) Cultured DRG neuron soma from naive Sprague Dawley (CTRL) rats were incubated with unconditioned CTRL, WT, or Fabry-SCM overnight, then washed out prior to current clamp electrophysiology recordings. (B) Neurons exposed to Fabry-SCM demonstrated significantly depolarized RMPs. (C) Representative traces of spontaneous firing from neurons incubated with CTRL, WT, and Fabry-SCM over 2 minutes. (D) Incubation of Fabry-SCM caused more neurons to exhibit spontaneous activity. Neurons that fired 1 or more action potentials at RMP were considered spontaneously active. (E) Current protocol and representative current-evoked traces from neurons exposed to CTRL-SCM, WT-SCM, or Fabry-SCM undergoing stimulation of 150 pA above rheobase for 500 ms. (F) Fabry-SCM enhanced the firing frequency of neurons compared with neurons exposed to WT- or CTRL-SCM. WT- and Fabry-SCM derived from n = 5 individual animal Schwann cell cultures per genotype. (B) n = 51–60 neurons per treatment from 21 animals; (C and D) n = 23–29 neurons per treatment from 8 animals; (E and F) n = 28–31 neurons per treatment from 13 animals. Data reported as (B and F) mean ± SEM, (D) mean. (B) One-way ANOVA with Bonferroni post hoc comparison and (F) 2-way repeated measures ANOVA with main effect of treatment (*** P < 0.0001). (D) χ2 with corrected Fisher’s exact post hoc comparison. * P < 0.05, ** P < 0.01, *** P < 0.001. SCM, Schwann cell–conditioned media; AP, action potential.