SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights

Autores
Rebelo, Adriana P.; Abad, Clemer; Dohrn, Maike F.; Li, Jian J.; Tieu, Ethan K.; Medina, Jessica; Yanick, Christopher; Huang, Jingyu; Zotter, Brendan; Young, Juan; Saporta, Mario; Scherer, Steven S.; Walz, Katherina; Zuchner, Stephan
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at ~7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding – enlarged “ballooned” myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.
Fil: Rebelo, Adriana P.. University of Miami; Estados Unidos
Fil: Abad, Clemer. University of Miami; Estados Unidos
Fil: Dohrn, Maike F.. RWTH Aachen University; Alemania. University of Miami; Estados Unidos
Fil: Li, Jian J.. University of Pennsylvania; Estados Unidos
Fil: Tieu, Ethan K.. University of Miami; Estados Unidos
Fil: Medina, Jessica. University of Miami; Estados Unidos
Fil: Yanick, Christopher. University of Miami; Estados Unidos
Fil: Huang, Jingyu. University of Miami; Estados Unidos
Fil: Zotter, Brendan. University of Pennsylvania; Estados Unidos
Fil: Young, Juan. University of Miami; Estados Unidos
Fil: Saporta, Mario. University of Miami; Estados Unidos
Fil: Scherer, Steven S.. University of Pennsylvania; Estados Unidos
Fil: Walz, Katherina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. University of Miami; Estados Unidos
Fil: Zuchner, Stephan. University of Miami; Estados Unidos
Materia
SORD
CMT
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/267138

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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insightsRebelo, Adriana P.Abad, ClemerDohrn, Maike F.Li, Jian J.Tieu, Ethan K.Medina, JessicaYanick, ChristopherHuang, JingyuZotter, BrendanYoung, JuanSaporta, MarioScherer, Steven S.Walz, KatherinaZuchner, StephanSORDCMThttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at ~7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding – enlarged “ballooned” myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.Fil: Rebelo, Adriana P.. University of Miami; Estados UnidosFil: Abad, Clemer. University of Miami; Estados UnidosFil: Dohrn, Maike F.. RWTH Aachen University; Alemania. University of Miami; Estados UnidosFil: Li, Jian J.. University of Pennsylvania; Estados UnidosFil: Tieu, Ethan K.. University of Miami; Estados UnidosFil: Medina, Jessica. University of Miami; Estados UnidosFil: Yanick, Christopher. University of Miami; Estados UnidosFil: Huang, Jingyu. University of Miami; Estados UnidosFil: Zotter, Brendan. University of Pennsylvania; Estados UnidosFil: Young, Juan. University of Miami; Estados UnidosFil: Saporta, Mario. University of Miami; Estados UnidosFil: Scherer, Steven S.. University of Pennsylvania; Estados UnidosFil: Walz, Katherina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. University of Miami; Estados UnidosFil: Zuchner, Stephan. University of Miami; Estados UnidosOxford University Press2024-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/267138Rebelo, Adriana P.; Abad, Clemer; Dohrn, Maike F.; Li, Jian J.; Tieu, Ethan K.; et al.; SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights; Oxford University Press; Brain; 147; 9; 9-2024; 3131-31430006-8950CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awae079/7636456info:eu-repo/semantics/altIdentifier/doi/10.1093/brain/awae079info:eu-repo/semantics/altIdentifier/url/https://www.biorxiv.org/content/10.1101/2023.12.05.570001v1info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:58:08Zoai:ri.conicet.gov.ar:11336/267138instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:58:08.74CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights
title SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights
spellingShingle SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights
Rebelo, Adriana P.
SORD
CMT
title_short SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights
title_full SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights
title_fullStr SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights
title_full_unstemmed SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights
title_sort SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights
dc.creator.none.fl_str_mv Rebelo, Adriana P.
Abad, Clemer
Dohrn, Maike F.
Li, Jian J.
Tieu, Ethan K.
Medina, Jessica
Yanick, Christopher
Huang, Jingyu
Zotter, Brendan
Young, Juan
Saporta, Mario
Scherer, Steven S.
Walz, Katherina
Zuchner, Stephan
author Rebelo, Adriana P.
author_facet Rebelo, Adriana P.
Abad, Clemer
Dohrn, Maike F.
Li, Jian J.
Tieu, Ethan K.
Medina, Jessica
Yanick, Christopher
Huang, Jingyu
Zotter, Brendan
Young, Juan
Saporta, Mario
Scherer, Steven S.
Walz, Katherina
Zuchner, Stephan
author_role author
author2 Abad, Clemer
Dohrn, Maike F.
Li, Jian J.
Tieu, Ethan K.
Medina, Jessica
Yanick, Christopher
Huang, Jingyu
Zotter, Brendan
Young, Juan
Saporta, Mario
Scherer, Steven S.
Walz, Katherina
Zuchner, Stephan
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv SORD
CMT
topic SORD
CMT
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at ~7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding – enlarged “ballooned” myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.
Fil: Rebelo, Adriana P.. University of Miami; Estados Unidos
Fil: Abad, Clemer. University of Miami; Estados Unidos
Fil: Dohrn, Maike F.. RWTH Aachen University; Alemania. University of Miami; Estados Unidos
Fil: Li, Jian J.. University of Pennsylvania; Estados Unidos
Fil: Tieu, Ethan K.. University of Miami; Estados Unidos
Fil: Medina, Jessica. University of Miami; Estados Unidos
Fil: Yanick, Christopher. University of Miami; Estados Unidos
Fil: Huang, Jingyu. University of Miami; Estados Unidos
Fil: Zotter, Brendan. University of Pennsylvania; Estados Unidos
Fil: Young, Juan. University of Miami; Estados Unidos
Fil: Saporta, Mario. University of Miami; Estados Unidos
Fil: Scherer, Steven S.. University of Pennsylvania; Estados Unidos
Fil: Walz, Katherina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. University of Miami; Estados Unidos
Fil: Zuchner, Stephan. University of Miami; Estados Unidos
description Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at ~7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding – enlarged “ballooned” myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.
publishDate 2024
dc.date.none.fl_str_mv 2024-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/267138
Rebelo, Adriana P.; Abad, Clemer; Dohrn, Maike F.; Li, Jian J.; Tieu, Ethan K.; et al.; SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights; Oxford University Press; Brain; 147; 9; 9-2024; 3131-3143
0006-8950
CONICET Digital
CONICET
url http://hdl.handle.net/11336/267138
identifier_str_mv Rebelo, Adriana P.; Abad, Clemer; Dohrn, Maike F.; Li, Jian J.; Tieu, Ethan K.; et al.; SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights; Oxford University Press; Brain; 147; 9; 9-2024; 3131-3143
0006-8950
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awae079/7636456
info:eu-repo/semantics/altIdentifier/doi/10.1093/brain/awae079
info:eu-repo/semantics/altIdentifier/url/https://www.biorxiv.org/content/10.1101/2023.12.05.570001v1
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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