Ion Channels and Pain in Fabry Disease

Overview

Journal Mol Pain

Date 2021 Jul 21

PMID 34284652

Citations 7

Authors

Carina Weissmann

Adriana A Albanese

Natalia E Contreras

Maria N Gobetto

Libia C Salinas Castellanos

Osvaldo D Uchitel

Affiliations

Soon will be listed here.

Abstract

Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A (α-Gal A) activity which results in progressive accumulation of globotriaosylceramide (Gb3) and related metabolites. One prominent feature of Fabry disease is neuropathic pain. Accumulation of Gb3 has been documented in dorsal root ganglia (DRG) as well as other neurons, and has lately been associated with the mechanism of pain though the pathophysiology is still unclear. Small fiber (SF) neuropathy in FD differs from other entities in several aspects related to the perception of pain, alteration of fibers as well as drug therapies used in the practice with patients, with therapies far from satisfying. In order to develop better treatments, more information on the underlying mechanisms of pain is needed. Research in neuropathy has gained momentum from the development of preclinical models where different aspects of pain can be modelled and further analyzed. This review aims at describing the different in vitro and FD animal models that have been used so far, as well as some of the insights gained from their use. We focus especially in recent findings associated with ion channel alterations -that apart from the vascular alterations-, could provide targets for improved therapies in pain.

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References

Ohshima T, Murray G, Swaim W, Longenecker G, Quirk J, Cardarelli C . alpha-Galactosidase A deficient mice: a model of Fabry disease. Proc Natl Acad Sci U S A. 1997; 94(6):2540-4. PMC: 20124. DOI: 10.1073/pnas.94.6.2540. View

Calvo M, Davies A, Hebert H, Weir G, Chesler E, Finnerup N . The Genetics of Neuropathic Pain from Model Organisms to Clinical Application. Neuron. 2019; 104(4):637-653. PMC: 6868508. DOI: 10.1016/j.neuron.2019.09.018. View

Zhu X, Yin L, Theisen M, Zhuo J, Siddiqui S, Levy B . Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates. Am J Hum Genet. 2019; 104(4):625-637. PMC: 6451694. DOI: 10.1016/j.ajhg.2019.02.003. View

Lipscombe D, Lopez-Soto E . Epigenetic control of ion channel expression and cell-specific splicing in nociceptors: Chronic pain mechanisms and potential therapeutic targets. Channels (Austin). 2020; 15(1):156-164. PMC: 7808434. DOI: 10.1080/19336950.2020.1860383. View

Rozenfeld P, Feriozzi S . Contribution of inflammatory pathways to Fabry disease pathogenesis. Mol Genet Metab. 2017; 122(3):19-27. DOI: 10.1016/j.ymgme.2017.09.004. View

Aerts J, Groener J, Kuiper S, Donker-Koopman W, Strijland A, Ottenhoff R . Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A. 2008; 105(8):2812-7. PMC: 2268542. DOI: 10.1073/pnas.0712309105. View

Benjamin E, Valle M, Wu X, Katz E, Pruthi F, Bond S . The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat. Genet Med. 2016; 19(4):430-438. PMC: 5392595. DOI: 10.1038/gim.2016.122. View

Wilson S, Mogil J . Measuring pain in the (knockout) mouse: big challenges in a small mammal. Behav Brain Res. 2001; 125(1-2):65-73. DOI: 10.1016/s0166-4328(01)00281-9. View

Klein M, Oaklander A . Ion channels and neuropathic pain. Elife. 2018; 7. PMC: 6255389. DOI: 10.7554/eLife.42849. View

10.

Schuller Y, Linthorst G, Hollak C, van Schaik I, Biegstraaten M . Pain management strategies for neuropathic pain in Fabry disease--a systematic review. BMC Neurol. 2016; 16:25. PMC: 4766720. DOI: 10.1186/s12883-016-0549-8. View

11.

Bradman M, Ferrini F, Salio C, Merighi A . Practical mechanical threshold estimation in rodents using von Frey hairs/Semmes-Weinstein monofilaments: Towards a rational method. J Neurosci Methods. 2015; 255:92-103. DOI: 10.1016/j.jneumeth.2015.08.010. View

12.

Lakoma J, Rimondini R, Donadio V, Liguori R, Caprini M . Pain related channels are differentially expressed in neuronal and non-neuronal cells of glabrous skin of fabry knockout male mice. PLoS One. 2014; 9(10):e108641. PMC: 4206276. DOI: 10.1371/journal.pone.0108641. View

13.

Liebau M, Braun F, Hopker K, Weitbrecht C, Bartels V, Muller R . Dysregulated autophagy contributes to podocyte damage in Fabry's disease. PLoS One. 2013; 8(5):e63506. PMC: 3656911. DOI: 10.1371/journal.pone.0063506. View

14.

Taguchi A, Maruyama H, Nameta M, Yamamoto T, Matsuda J, Kulkarni A . A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis. Biochem J. 2013; 456(3):373-83. PMC: 4160053. DOI: 10.1042/BJ20130825. View

15.

Eijkenboom I, Sopacua M, Otten A, Gerrits M, Hoeijmakers J, Waxman S . Expression of pathogenic SCN9A mutations in the zebrafish: A model to study small-fiber neuropathy. Exp Neurol. 2018; 311:257-264. DOI: 10.1016/j.expneurol.2018.10.008. View

16.

Golden J, Hoshi M, Nassar M, Enomoto H, Wood J, Milbrandt J . RET signaling is required for survival and normal function of nonpeptidergic nociceptors. J Neurosci. 2010; 30(11):3983-94. PMC: 2850282. DOI: 10.1523/JNEUROSCI.5930-09.2010. View

17.

Gerlai R . Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype?. Trends Neurosci. 1996; 19(5):177-81. DOI: 10.1016/s0166-2236(96)20020-7. View

18.

Saito S, Ohno K, Sakuraba H . Fabry-database.org: database of the clinical phenotypes, genotypes and mutant α-galactosidase A structures in Fabry disease. J Hum Genet. 2011; 56(6):467-8. DOI: 10.1038/jhg.2011.31. View

19.

Jabbarzadeh-Tabrizi S, Boutin M, Day T, Taroua M, Schiffmann R, Auray-Blais C . Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model. J Lipid Res. 2020; 61(11):1410-1423. PMC: 7604726. DOI: 10.1194/jlr.RA120000909. View

20.

Uceyler N, Biko L, Hose D, Hofmann L, Sommer C . Comprehensive and differential long-term characterization of the alpha-galactosidase A deficient mouse model of Fabry disease focusing on the sensory system and pain development. Mol Pain. 2016; 12. PMC: 4956180. DOI: 10.1177/1744806916646379. View