title: Pain related channels are differentially expressed in neuronal and non-neuronal cells of glabrous skin of fabry knockout male mice.
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 null 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.
authors.affiliation: Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Lakomá
authors.affiliation: Department of Medical and Clinical Sciences (DIMEC), University of Bologna, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rimondini
authors.affiliation: IRCCS Institute of Neurological Sciences, AUSL Bologna, Bologna, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Donadio
authors.affiliation: IRCCS Institute of Neurological Sciences, AUSL Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.affiliation: Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Caprini
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000096:biosynthesis; D009437:Neuralgia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012867:Skin / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D050916:TRPV Cation Channels / Q000096:biosynthesis; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000519:alpha-Galactosidase