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Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels

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Abstract

Globoid cell leukodystrophy (GLD; Krabbe’s disease), caused by a genetic galactosylceramidase deficiency, affects both the central and peripheral nervous systems (CNS and PNS). Allogenic hematopoietic stem-cell transplantation (HSCT) has been beneficial for clinical improvement of this disease. However, recent reports by Siddiqi et al. suggested that none of their transplanted patients achieved complete normalization of their peripheral nerve function, despite the well-documented remyelination of the CNS and PNS in the treated patients. We hypothesized that the PNS dysfunction in GLD is due to altered Schwann cell–axon interactions, resulting in structural abnormalities of the node of Ranvier and aberrant expression of ion channels caused by demyelination and that the persistence of this altered interaction is responsible for the dysfunction of the PNS after HSCT. Since there has not been any investigation of the Schwann cell–axonal relationship in twitcher mice, an authentic model of GLD, we first investigated structural abnormalities, focusing on the node of Ranvier in untreated twitcher mice, and compared the results with those obtained after receiving bone marrow transplantation (BMT). As expected, we found numerous supernumerary Schwann cells that formed structurally abnormal nodes of Ranvier. Similar findings, though at somewhat variable extent, were detected in mice treated with BMT. Activated supernumerary Schwann cells expressed GFAP immunoreactivity and generated Alcian blue-positive extracellular matrix (ECM) in the endoneurial space. The processes of these supernumerary Schwann cells often covered and obliterated the nodal regions. Furthermore, the distribution of Na+ channel immunoreactivity was diffuse without the concentration at the nodes of Ranvier as seen in wild-type mice. Neither K+ channels nor Neurexin IV/ Caspr/ Paranoidin (NCP-1) were detected in the twi/twi sciatic nerve. The results of our study suggest the importance of normalization of the Schwann cell–axon relationship for the functional recovery of peripheral nerves, when one considers therapeutic strategies for PNS pathology in GLD.

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Acknowledgments

We thank Mrs. Clarita Langaman for assisting in the electron microscopy. This work was supported by United States Public Health Service Grants NS-24453 and HD-03110 (K.S.); Ministry of Education, Culture, Sports, Science, and Technology of Japan Grants 18790715 (K.K.S.), 09670806 (M.T.); Osaka Medical Research Foundation for Incurable Diseases (M.T.); and by a research grant from Japan Foundation for Applied Enzymology (I.M.).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Kuriko Kagitani-Shimono, Ikuko Mohri, Takashi Yagi & Kinuko Suzuki

  2. Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Kuriko Kagitani-Shimono

  3. Department of Mental Health and Environmental Effects Research, Molecular Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Osaka, Japan

    Ikuko Mohri & Masako Taniike

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  1. Kuriko Kagitani-Shimono
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Correspondence to Kuriko Kagitani-Shimono.

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Kagitani-Shimono, K., Mohri, I., Yagi, T. et al. Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels. Acta Neuropathol 115, 577–587 (2008). https://doi.org/10.1007/s00401-007-0333-3

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