Gaucher Disease: a Hyper-Hippo Syndrome?

The Gaucher Disease (GD) is a lysosomal disorder associated with mutations in the GBA1 gene, encoding the acidic β-glucocerebrosidase. GD is characterized by a wide spectrum of phenotypic manifestations, the most severe of which involve the nervous system, with massive neuronal loss and microglial proliferation. Different symptoms are also observed in individuals bearing identical GBA1 mutations, suggesting that additional players are involved in the disease. Our hypothesis is that hyper-activation of the Hippo pathway, recently found involved in some neurodegenerative syndromes, may contribute to the dramatic outcome of the neuronopathic GD. We thus started an expression analysis of upstream and downstream Hippo pathway components in Drosophila GBA1-deficient larval and adult organs. While some Hippo downstream targets resulted down-regulated in GBA1-deficient tissues, both in terms of transcript and protein content, Fat, an atypical cadherin upstream of the kinase complex involved in the regulation of glial and synapse development, was found up-regulated. In the light of this latter result, we are currently performing behavioural assays in flies where GBA1 expression has been silenced in glial or neuronal cells, to find out possible cross-effects. Preliminary data will be presented about the implication of the Hippo pathway in the pathogenesis of the neuronopathic GD.