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

PLoS One. 2020 Jan 13;15(1):e0227077. doi: 10.1371/journal.pone.0227077. eCollection 2020.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Disease Models, Animal*
  • Female
  • Gaucher Disease / genetics*
  • Gaucher Disease / metabolism
  • Gaucher Disease / pathology
  • Glucosylceramidase / genetics*
  • Glucosylceramidase / metabolism
  • Leukocytes / pathology
  • Liver / metabolism
  • Liver / pathology
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Movement
  • Mutation
  • Neurons / metabolism
  • Neurons / pathology
  • Phenotype*
  • Spleen / metabolism
  • Spleen / pathology
  • Thymus Gland / metabolism
  • Thymus Gland / pathology

Substances

  • Glucosylceramidase

Grant support

QPS Austria GmbH provided support in the form of salaries for authors VS, ESM, SF, MF, TL, IS, MP, JN and BHP and covered material costs for animal housing, breeding, tissue sampling, behavioral analyses, GCase measurement and all histological analyses. Pronexus Analytical AB provided support in the form of salaries for authors SS and JK and covered material costs for Glucosylceramide and Glucosylsphingosine measurements. Both companies did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.