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

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


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


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