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Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease

Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct resu...

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Autores principales: Schiffer, Victoria, Santiago-Mujika, Estibaliz, Flunkert, Stefanie, Schmidt, Staffan, Farcher, Martina, Loeffler, Tina, Schilcher, Irene, Posch, Maria, Neddens, Joerg, Sun, Ying, Kehr, Jan, Hutter-Paier, Birgit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957154/
https://www.ncbi.nlm.nih.gov/pubmed/31929594
http://dx.doi.org/10.1371/journal.pone.0227077
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author Schiffer, Victoria
Santiago-Mujika, Estibaliz
Flunkert, Stefanie
Schmidt, Staffan
Farcher, Martina
Loeffler, Tina
Schilcher, Irene
Posch, Maria
Neddens, Joerg
Sun, Ying
Kehr, Jan
Hutter-Paier, Birgit
author_facet Schiffer, Victoria
Santiago-Mujika, Estibaliz
Flunkert, Stefanie
Schmidt, Staffan
Farcher, Martina
Loeffler, Tina
Schilcher, Irene
Posch, Maria
Neddens, Joerg
Sun, Ying
Kehr, Jan
Hutter-Paier, Birgit
author_sort Schiffer, Victoria
collection PubMed
description Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease.
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spelling pubmed-69571542020-01-26 Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease Schiffer, Victoria Santiago-Mujika, Estibaliz Flunkert, Stefanie Schmidt, Staffan Farcher, Martina Loeffler, Tina Schilcher, Irene Posch, Maria Neddens, Joerg Sun, Ying Kehr, Jan Hutter-Paier, Birgit PLoS One Research Article Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease. Public Library of Science 2020-01-13 /pmc/articles/PMC6957154/ /pubmed/31929594 http://dx.doi.org/10.1371/journal.pone.0227077 Text en © 2020 Schiffer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Schiffer, Victoria
Santiago-Mujika, Estibaliz
Flunkert, Stefanie
Schmidt, Staffan
Farcher, Martina
Loeffler, Tina
Schilcher, Irene
Posch, Maria
Neddens, Joerg
Sun, Ying
Kehr, Jan
Hutter-Paier, Birgit
Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease
title Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease
title_full Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease
title_fullStr Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease
title_full_unstemmed Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease
title_short Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease
title_sort characterization of the visceral and neuronal phenotype of 4l/ps-na mice modeling gaucher disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957154/
https://www.ncbi.nlm.nih.gov/pubmed/31929594
http://dx.doi.org/10.1371/journal.pone.0227077
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