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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Bibliographic Details
Published in:PloS one 2020, Vol.15 (1), p.e0227077-e0227077
Main Authors: 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
Format: Article
Language:English
Subjects:
Alterations
Animal diseases
Animal models
Animals
Biology and Life Sciences
Brain research
Calbindin
Cerebellum
Cerebellum - metabolism
Cerebellum - pathology
Disease
Disease Models, Animal
Female
Gaucher Disease - genetics
Gaucher Disease - metabolism
Gaucher Disease - pathology
Gaucher's disease
Gliosis
Glucosylceramidase
Glucosylceramidase - genetics
Glucosylceramidase - metabolism
Inflammation
Laboratory animals
Leukocytes
Leukocytes - pathology
Liver - metabolism
Liver - pathology
Lung - metabolism
Lung - pathology
Macrophages
Male
Medical treatment
Medicin och hälsovetenskap
Medicine and Health Sciences
Mice
Mice, Inbred C57BL
Microglia
Movement
Mutation
Neurons - metabolism
Neurons - pathology
Organs
Pathology
Pediatrics
Phenotype
Phenotypes
Research and Analysis Methods
Signs and symptoms
Spleen
Spleen - metabolism
Spleen - pathology
Substrates
Thymus Gland - metabolism
Thymus Gland - pathology
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0227077