Hippo and necroptosis pathways are involved in cell growth defects in Gaucher disease

Gaucher disease (GD) is a monogenic disorder characterized byβ-glucocerebrosidase enzyme deficiency. Typical features of the diseaseare the unrestrained activation of inflammatory mechanisms andneuronal cell death in neuronopathic conditions, whose molecularpathways are still not fully understood. Recent evidences show thatupregulation of the Hippo pathway is associated with neuroinflamma-tion and neuronal cell death. We analyzed the Hippo pathway activitytaking advantage of a Drosophila Gaucher-like model characterized bydGBA1b knock-out (GBA1bKO).WefoundderegulationofCycE,dIAPandMYC, direct targets of the pathway both in Drosophila and mammals,which were severely reduced at transcript and protein level,suggestingacell growth impairment. Analyzing upstream components we foundthat Fat, an atypical cadherin upstream of the kinase complex, wasupregulated. Moreover the glypicans Dally and Dally-like, known to benegatively regulated by Fat and involved in glial and synapsedevelopment, were found downregulated in the GBA1bKObackground,supporting a role in neurological damage. On the other hand, theaberrant inflammatory condition of the hematological compartmentwas investigated in the human model of induced Pluripotent Stem Cells(iPSC), differentiated into hematopoietic progenitors. While GD iPSCswere able to differentiate into CD34+/CD43+/CD45+ progenitors, theyshowed a decreased proliferative potential compared to healthy donoriPSC either in semisolid and liquid culture, therefore exhibiting a growthimpairment. This effect was coupled with the activation of necroptosispathway with a significant upregulation of RIPK3 and MLKL both in thepluripotent and differentiated state. Correction of the mutation to rescuethe phenotype is ongoing, taking advantage of AAVS1 editing approachin order to develop a fully comparable cell model useful in a cell therapyperspective. These data obtained with suitable GD models support therole of Hippo and necroptosis effectors in GD, amenable of furtherconsideration as potential therapeutic targets.