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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/267138
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oai:ri.conicet.gov.ar:11336/267138 |
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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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1844613734935298048 |
score |
13.070432 |