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.
Highlights
Gaucher disease (GD) is a sphingolipidosis and belongs to the large group of lysosomal storage diseases
Further analysis of motor deficits in the beam walk test revealed a significant increase of slips in 4L/prosaposin knockout (PS-)NA mice compared to controls at 12 week of age
Additional analysis of 4L/PS-NA mice for motor deficits in the Rota Rod test showed a significantly reduced latency to fall off the rod at the age of 18 weeks compared to controls
Summary
Gaucher disease (GD) is a sphingolipidosis and belongs to the large group of lysosomal storage diseases. There are several GD mouse models available that are based on different disease aspects like depleted or reduced prosaposin expression [5, 6], Gba deletion [7, 8] or Gba point mutations [9, 10]. Major issues of these models are severely reduced life spans or weak pathological features, making these models impracticable for treatment studies. Glucosylsphingosine a biomarker of GD [12] is 20-117-fold increased in these same regions [13]
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