CBE treatment of alpha-synuclein over-expressing and wildtype mice models Gaucher disease pathology

Abstract

Gaucher disease is the most prevalent lysosomal storage disorder and is caused by autosomal recessive mutations in the glucocerebrosidase gene. Glucocerebrosidase (GCase) hydrolyses the sphingolipid glucoceramide to glucose and ceramide. Deficiency in GCase activity leads to a multisystemic accumulation of substrate in lysosomes. Additionally, α-synuclein, tau, ubiquitin, APP and Abeta might build up in affected tissues. Most of these proteins are also accumulated in several other rare diseases and neurodegenerative diseases such as α-synuclein in dementia with Lewy bodies or Parkinson´s disease. In the last years several links between α-synucleinopathies and lysosomal storage diseases have been reported. We thus combined an inducible mouse Gaucher model with a transgenic Parkinson´s disease mouse by treating six months old alpha-syunclein transgenic mice and non-transgenic littermates with Conduritol B Epoxide (CBE) that serves as an irreversible inhibitor of β-glucosidase and is known to cause a Gaucher-like phenotype. After CBE treatment, animals were tested for motor impairments in the Beam Walk test und brain tissue was analyzed for alpha-synuclein expression, activated microglia and astrocytosis by alpha-synuclein, Iba1 and GFAP immunofluorescent labeling. Our results show that CBE treatment caused motor impairments that were not affected by the transgene. Alpha-synuclein levels were highly increased in transgenic animals compared to non-transgenic littermates and CBE treatment caused a further increase of alpha-synuclein levels. Activated microglia and astrogliosis were increased in all CBE treated groups, independent of the transgene. Our data validate motor impairments and neuroinflammation after CBE treatment and additionally show an impact of CBE on alpha-synuclein levels in transgenic mice. Using alpha-synuclein transgenic mice to induce Gaucher disease by CBE treatment might therefore be a valuable alternative to the already established CBE model in wildtype mice by combining pathologies observed in Gaucher and Parkinson disease.