{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:46Z","timestamp":1787027866335,"version":"build-2736575974"},"reference-count":66,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T00:00:00Z","timestamp":1653350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["SFB1158"],"award-info":[{"award-number":["SFB1158"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["N-375"],"award-info":[{"award-number":["N-375"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["UE171\/15-1"],"award-info":[{"award-number":["UE171\/15-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Interdisciplinary Center for Clinical Research W\u00fcrzburg","award":["SFB1158"],"award-info":[{"award-number":["SFB1158"]}]},{"name":"Interdisciplinary Center for Clinical Research W\u00fcrzburg","award":["N-375"],"award-info":[{"award-number":["N-375"]}]},{"name":"Interdisciplinary Center for Clinical Research W\u00fcrzburg","award":["UE171\/15-1"],"award-info":[{"award-number":["UE171\/15-1"]}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["SFB1158"],"award-info":[{"award-number":["SFB1158"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["N-375"],"award-info":[{"award-number":["N-375"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["UE171\/15-1"],"award-info":[{"award-number":["UE171\/15-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (&lt;6 months) (p &lt; 0.01) and old (\u226512 months) (p &lt; 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206+ macrophages (p &lt; 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p &lt; 0.05), IL10 (p &lt; 0.001), glial fibrillary acidic protein (GFAP) (p &lt; 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p &lt; 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1+ DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p &lt; 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p &lt; 0.01) and old (p &lt; 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p &lt; 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p &lt; 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p &lt; 0.001) and old (p &lt; 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.<\/jats:p>","DOI":"10.3390\/cells11111730","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T22:04:06Z","timestamp":1653429846000},"page":"1730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Dysregulation of Immune Response Mediators and Pain-Related Ion Channels Is Associated with Pain-like Behavior in the GLA KO Mouse Model of Fabry Disease"],"prefix":"10.3390","volume":"11","author":[{"given":"Marlene","family":"Spitzel","sequence":"first","affiliation":[{"name":"Department of Neurology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Breyer","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9496-9266","authenticated-orcid":false,"given":"Dorothea","family":"Henniger","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehtap","family":"Bayin","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1225-4633","authenticated-orcid":false,"given":"Daniela","family":"Mauceri","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7064-5002","authenticated-orcid":false,"given":"Claudia","family":"Sommer","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6973-6428","authenticated-orcid":false,"given":"Nurcan","family":"\u00dc\u00e7eyler","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1136\/postgradmedj-2018-136056","article-title":"Hot topics in Fabry disease","volume":"94","author":"Cairns","year":"2018","journal-title":"Postgrad. 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