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

English version

Autoři: Victoria Schiffer ^aff001; Estibaliz Santiago-Mujika ^aff001; Stefanie Flunkert ^aff001; Staffan Schmidt ^aff002; Martina Farcher ^aff001; Tina Loeffler ^aff001; Irene Schilcher ^aff001; Maria Posch ^aff001; Joerg Neddens ^aff001; Ying Sun ^aff003; Jan Kehr ^aff002; Birgit Hutter-Paier ^aff001
Působiště autorů: QPS Austria GmbH, Neuropharmacology, Grambach, Austria ^aff001; Pronexus Analytical AB, Bromma, Sweden ^aff002; Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America ^aff003; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America ^aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227077

Souhrn

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.

Klíčová slova:

Animal models of disease – Cerebellum – Hippocampus – Macrophages – Mouse models – Spleen – Thymus – White blood cells

Zdroje

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

Souhrn

Klíčová slova:

Zdroje

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