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Pain related channels are differentially expressed in neuronal and non-neuronal cells of glabrous skin of fabry knockout male mice.

Lakomá J, Rimondini R, Donadio V, Liguori R, Caprini M - PLoS ONE (2014)

Bottom Line: Additionally, KO mice showed a decreased and scattered pattern of neuronal terminations consistent with the reduction in neuronal terminations in skin biopsies of patients with small fiber neuropathies.At the molecular level KO animals showed an increase in the expression of TRPV1 and Nav1.8, and a decrease in the expression of TRPM8.Notably, these alterations are observed in young animals.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.

ABSTRACT
Fabry disease (FD) is one of the X-linked lysosomal storage disorders caused by deficient functioning of the alpha-galactosidase A (α-GalA) enzyme. The α-GalA deficiency leads to multi-systemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide in the endothelium and vascular smooth muscles. A hallmark symptom of FD patients is peripheral pain that appears in the early stage of the disease. Pain in FD patients is a peripheral small-fiber idiopathic neuropathy, with intra-epidermal fiber density and integrity being used for diagnosing FD in humans. However, the molecular correlates underlying pain sensation in FD remain elusive. Here, we have employed the α-GalA gene KO mouse as a model of FD in rodents to investigate molecular changes in their peripheral nervous system that may account for their algesic symptoms. The α-GalA mice display neuropathic pain as evidenced by thermal hyperalgesia and mechanical allodynia, with histological analyses showing alterations in cutaneous innervation. Additionally, KO mice showed a decreased and scattered pattern of neuronal terminations consistent with the reduction in neuronal terminations in skin biopsies of patients with small fiber neuropathies. At the molecular level KO animals showed an increase in the expression of TRPV1 and Nav1.8, and a decrease in the expression of TRPM8. Notably, these alterations are observed in young animals. Taken together, our findings imply that the α-GalA KO mouse is a good model in which to study the peripheral small fiber neuropathy exhibited by FD patients, and provides molecular evidence for a hyperexcitability of small nociceptors in FD.

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The expression of TRPV1 in epidermal neuronal fibers of α-GalA KO males frontal paws.The evaluation of co-localization of TRPV1 and PGP 9.5 expression in 50 µm floating sagittal sections of WT (A) and α-GalA KO (B) males (n = 4) revealed similar values of Pearson's coefficient in both α-GalA WT males (PWT = 0.35) and KO (PKO = 0.29), (p = 0.1132). The TRPV1 receptor is expressed in neuronal fibers of WT (C left panel) males marked by specific antibody PGP 9.5 with the high intensity as it is expressed in α-GalA KO (D left panel). The co-localization of both markers (C, D right panels) revealed similar results. Panels C, D were enhanced with 1.125 zoom respectively to square area in panels A, B. Scale bars represent 100 µm.
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pone-0108641-g006: The expression of TRPV1 in epidermal neuronal fibers of α-GalA KO males frontal paws.The evaluation of co-localization of TRPV1 and PGP 9.5 expression in 50 µm floating sagittal sections of WT (A) and α-GalA KO (B) males (n = 4) revealed similar values of Pearson's coefficient in both α-GalA WT males (PWT = 0.35) and KO (PKO = 0.29), (p = 0.1132). The TRPV1 receptor is expressed in neuronal fibers of WT (C left panel) males marked by specific antibody PGP 9.5 with the high intensity as it is expressed in α-GalA KO (D left panel). The co-localization of both markers (C, D right panels) revealed similar results. Panels C, D were enhanced with 1.125 zoom respectively to square area in panels A, B. Scale bars represent 100 µm.

Mentions: Next, we examined whether the activation of high temperature perception pathway revealed by the behavioral experiment was due to an over expression of TRPV1 receptor specifically in the epidermal nerve fibers. To this end, we performed co-localization analysis between epidermal endings of PGP 9.5 positive neuronal fibers glabrous skin of frontal paw of KO and WT and TRPV1 receptors (Figure 6p = 0.1132, n = 3 animals for WT, n = 3 animals for KO). The Pearson correlation coefficients expressed as a P value for PWT = 0.35 and PKO = 0.29 suggest that the co-localization of TRPV1 and PGP 9.5 in neural fibers of α-GalA(−/0) mice paw glabrous skin was similar in both investigated groups of animals. On the contrary, TRPM8 was omitted since the strong decrease of receptor detection in the α-GalA KO mouse model.


Pain related channels are differentially expressed in neuronal and non-neuronal cells of glabrous skin of fabry knockout male mice.

Lakomá J, Rimondini R, Donadio V, Liguori R, Caprini M - PLoS ONE (2014)

The expression of TRPV1 in epidermal neuronal fibers of α-GalA KO males frontal paws.The evaluation of co-localization of TRPV1 and PGP 9.5 expression in 50 µm floating sagittal sections of WT (A) and α-GalA KO (B) males (n = 4) revealed similar values of Pearson's coefficient in both α-GalA WT males (PWT = 0.35) and KO (PKO = 0.29), (p = 0.1132). The TRPV1 receptor is expressed in neuronal fibers of WT (C left panel) males marked by specific antibody PGP 9.5 with the high intensity as it is expressed in α-GalA KO (D left panel). The co-localization of both markers (C, D right panels) revealed similar results. Panels C, D were enhanced with 1.125 zoom respectively to square area in panels A, B. Scale bars represent 100 µm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4206276&req=5

pone-0108641-g006: The expression of TRPV1 in epidermal neuronal fibers of α-GalA KO males frontal paws.The evaluation of co-localization of TRPV1 and PGP 9.5 expression in 50 µm floating sagittal sections of WT (A) and α-GalA KO (B) males (n = 4) revealed similar values of Pearson's coefficient in both α-GalA WT males (PWT = 0.35) and KO (PKO = 0.29), (p = 0.1132). The TRPV1 receptor is expressed in neuronal fibers of WT (C left panel) males marked by specific antibody PGP 9.5 with the high intensity as it is expressed in α-GalA KO (D left panel). The co-localization of both markers (C, D right panels) revealed similar results. Panels C, D were enhanced with 1.125 zoom respectively to square area in panels A, B. Scale bars represent 100 µm.
Mentions: Next, we examined whether the activation of high temperature perception pathway revealed by the behavioral experiment was due to an over expression of TRPV1 receptor specifically in the epidermal nerve fibers. To this end, we performed co-localization analysis between epidermal endings of PGP 9.5 positive neuronal fibers glabrous skin of frontal paw of KO and WT and TRPV1 receptors (Figure 6p = 0.1132, n = 3 animals for WT, n = 3 animals for KO). The Pearson correlation coefficients expressed as a P value for PWT = 0.35 and PKO = 0.29 suggest that the co-localization of TRPV1 and PGP 9.5 in neural fibers of α-GalA(−/0) mice paw glabrous skin was similar in both investigated groups of animals. On the contrary, TRPM8 was omitted since the strong decrease of receptor detection in the α-GalA KO mouse model.

Bottom Line: Additionally, KO mice showed a decreased and scattered pattern of neuronal terminations consistent with the reduction in neuronal terminations in skin biopsies of patients with small fiber neuropathies.At the molecular level KO animals showed an increase in the expression of TRPV1 and Nav1.8, and a decrease in the expression of TRPM8.Notably, these alterations are observed in young animals.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.

ABSTRACT
Fabry disease (FD) is one of the X-linked lysosomal storage disorders caused by deficient functioning of the alpha-galactosidase A (α-GalA) enzyme. The α-GalA deficiency leads to multi-systemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide in the endothelium and vascular smooth muscles. A hallmark symptom of FD patients is peripheral pain that appears in the early stage of the disease. Pain in FD patients is a peripheral small-fiber idiopathic neuropathy, with intra-epidermal fiber density and integrity being used for diagnosing FD in humans. However, the molecular correlates underlying pain sensation in FD remain elusive. Here, we have employed the α-GalA gene KO mouse as a model of FD in rodents to investigate molecular changes in their peripheral nervous system that may account for their algesic symptoms. The α-GalA mice display neuropathic pain as evidenced by thermal hyperalgesia and mechanical allodynia, with histological analyses showing alterations in cutaneous innervation. Additionally, KO mice showed a decreased and scattered pattern of neuronal terminations consistent with the reduction in neuronal terminations in skin biopsies of patients with small fiber neuropathies. At the molecular level KO animals showed an increase in the expression of TRPV1 and Nav1.8, and a decrease in the expression of TRPM8. Notably, these alterations are observed in young animals. Taken together, our findings imply that the α-GalA KO mouse is a good model in which to study the peripheral small fiber neuropathy exhibited by FD patients, and provides molecular evidence for a hyperexcitability of small nociceptors in FD.

Show MeSH
Related in: MedlinePlus