Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model

Abstract

Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3) in the endothelium and vascular smooth muscles. A hallmark symptom of Fabry disease patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. The α-GalA gene null mouse model (α-GalA(−/0)) has provided molecular evidence for the molecular alterations in small type-C nociceptors in Fabry disease that may underlie their hyperexcitability, although the specific mechanism remains elusive. Here, we have addressed this question and report that small type-C nociceptors from α-GalA(−/0) mice exhibit a significant increase in the expression and function of the TRPV1 channel, a thermoTRP channel implicated in painful heat sensation. Notably, male α-GalA(−/0) mice displayed a ≈2-fold higher heat sensitivity than wild-type animals, consistent with the augmented expression levels and activity of TRPV1 in α-GalA(−/0) nociceptors. Intriguingly, blockade of neuronal exocytosis with peptide DD04107, a process that inhibits among others the algesic membrane recruitment of TRPV1 channels in peptidergic nociceptors, virtually eliminated the enhanced heat nociception of α-GalA(−/0) mice. Together, these findings suggest that the augmented expression of TRPV1 in α-GalA(−/0) nociceptors may underly at least in part their increased heat sensitivity, and imply that blockade of peripheral neuronal exocytosis may be a valuable pharmacological strategy to reduce pain in Fabry disease patients, increasing their quality of life.

Altered globotriaosylceramide accumulation and mucosal neuronal fiber density in the colon of the Fabry disease mouse model

“…Therefore, even if the underlying pathophysiology has not been extensively investigated, it is reasonable to hypothesize an involvement of myenteric plexus and smooth muscle cells in the onset of the GI symptoms of FD. Moreover, we reported that the expression of neuronal marker PGP9.5 showed a significant decreased and scattered pattern of neuronal terminations in the frontal skin paw of α‐Gal A −/0 mice, in comparison with their α‐Gal A +/0 littermates . This finding mirrors the decrease in neuronal terminations marked by PGP9.5 in skin biopsies of human patients with small fiber .…”

“…decreased and scattered pattern of neuronal terminations in the frontal skin paw of α-Gal A −/0 mice, in comparison with their α-Gal A +/0 littermates 51. This finding mirrors the decrease in neuronal terminations marked by PGP9.5 in skin biopsies of human patients with small fiber 11,55.…”

“…Different groups previously described Gb3 accumulation in DRG neurons as a key factor for the altered pain and thermal sensitivity . In fact, Gb3 accumulation leads to an impaired cellular function, such as limited contractility of muscular cells, and, in turn, to an altered expression of ion channels . Recently, chronic intestinal pseudo‐obstruction was reported in a patient group as a result of substrate deposition at autonomic ganglia and smooth muscle cell level .…”

“…Gb3 accumulation leads to an impaired cellular function, such as limited contractility of muscular cells, and, in turn, to an altered expression of ion channels. 17,[50][51][52][53] Recently, chronic intestinal pseudoobstruction was reported in a patient group as a result of substrate deposition at autonomic ganglia and smooth muscle cell level. 36,54 These alterations could trigger secondary pathological processes reflecting a tissue response (ie, hypertrophy).…”

Chronic intestinal pseudo-obstruction. Did you search for lysosomal storage diseases?

“…Intestinal ischaemia due myenteric vessel occlusion could also be correlated with the small fiber neuropathy as a result of vasa nervorum obliteration [4]. Animal models with FD showed mechanical hypersensitivity in the von- Frey test and mechanical allodynia when compared with controls [23], [24]. The same studies demonstrated that tissue involvement in DRG and small nerve fiber loss are linked with upregulation of sodium channels type 1.8 (Na v 1.8) and transient receptor potential vanilloid type 1 (TRPV1).…”