학술논문
Small fibre neuropathy in Fabry disease: a human-derived neuronal in vitro disease model and pilot data.
Document Type
Academic Journal
Author
Klein T; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Grüner J; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Breyer M; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Schlegel J; Department of Biotechnology and Biophysics, University of Würzburg, 97074 Würzburg, Germany.; Schottmann NM; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Hofmann L; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Gauss K; Medical Biophysics, Institute for Physiology and Pathophysiology, Heidelberg University, 69120 Heidelberg, Germany.; Mease R; Medical Biophysics, Institute for Physiology and Pathophysiology, Heidelberg University, 69120 Heidelberg, Germany.; Erbacher C; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Finke L; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Klein A; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Klug K; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Karl-Schöller F; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Vignolo B; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Reinhard S; Department of Biotechnology and Biophysics, University of Würzburg, 97074 Würzburg, Germany.; Schneider T; Institute for Human Genetics, University of Würzburg, 97074 Würzburg, Germany.; Günther K; Institute of Anatomy and Cell Biology, University of Würzburg, 97070 Würzburg, Germany.; Fink J; Institute of Organic Chemistry, University of Würzburg, 97074 Würzburg, Germany.; Dudek J; Comprehensive Heart Failure Center CHFC, University Hospital Würzburg, 97080 Würzburg, Germany.; Maack C; Comprehensive Heart Failure Center CHFC, University Hospital Würzburg, 97080 Würzburg, Germany.; Klopocki E; Institute for Human Genetics, University of Würzburg, 97074 Würzburg, Germany.; Seibel J; Institute of Organic Chemistry, University of Würzburg, 97074 Würzburg, Germany.; Edenhofer F; Institute of Anatomy and Cell Biology, University of Würzburg, 97070 Würzburg, Germany.; Wischmeyer E; Institute of Physiology, University of Würzburg, 97070 Würzburg, Germany.; Sauer M; Department of Biotechnology and Biophysics, University of Würzburg, 97074 Würzburg, Germany.; Üçeyler N; Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.; Würzburg Fabry Center for Interdisciplinary Therapy (FAZIT), University Hospital Würzburg, 97080 Würzburg, Germany.
Source
Publisher: Oxford University Press Country of Publication: England NLM ID: 101755125 Publication Model: eCollection Cited Medium: Internet ISSN: 2632-1297 (Electronic) Linking ISSN: 26321297 NLM ISO Abbreviation: Brain Commun Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
Acral burning pain triggered by fever, thermal hyposensitivity and skin denervation are hallmarks of small fibre neuropathy in Fabry disease, a life-threatening X-linked lysosomal storage disorder. Variants in the gene encoding alpha-galactosidase A may lead to impaired enzyme activity with cellular accumulation of globotriaosylceramide. To study the underlying pathomechanism of Fabry-associated small fibre neuropathy, we generated a neuronal in vitro disease model using patient-derived induced pluripotent stem cells from three Fabry patients and one healthy control. We further generated an isogenic control line via gene editing. We subjected induced pluripotent stem cells to targeted peripheral neuronal differentiation and observed intra-lysosomal globotriaosylceramide accumulations in somas and neurites of Fabry sensory neurons using super-resolution microscopy. At functional level, patch-clamp analysis revealed a hyperpolarizing shift of voltage-gated sodium channel steady-state inactivation kinetics in isogenic control neurons compared with healthy control neurons ( P < 0.001). Moreover, we demonstrate a drastic increase in Fabry sensory neuron calcium levels at 39°C mimicking clinical fever ( P < 0.001). This pathophysiological phenotype was accompanied by thinning of neurite calibres in sensory neurons differentiated from induced pluripotent stem cells derived from Fabry patients compared with healthy control cells ( P < 0.001). Linear-nonlinear cascade models fit to spiking responses revealed that Fabry cell lines exhibit altered single neuron encoding properties relative to control. We further observed mitochondrial aggregation at sphingolipid accumulations within Fabry sensory neurites utilizing a click chemistry approach together with mitochondrial dysmorphism compared with healthy control cells. We pioneer pilot insights into the cellular mechanisms contributing to pain, thermal hyposensitivity and denervation in Fabry small fibre neuropathy and pave the way for further mechanistic in vitro studies in Fabry disease and the development of novel treatment approaches.
Competing Interests: The authors report no competing interests.
(© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Competing Interests: The authors report no competing interests.
(© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)