Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

• DOI: 10.1038/s42003-023-04813-2
• Publication Date: 2023-04-19T11:02:21Z
• Authors: Daria Messelodi; Silvia Strocchi; Salvatore Nicola ...; Pascale Baden; Valentina Indio; Federico M. Giorgi; Alberto Taddia; Salvatore Serravalle; Sabrina Valente; Alessio di Fonzo; Emanuele Frattini; Roberto Bernardoni; Annalisa Pession; Daniela Grifoni; Michela Deleidi; Annalisa Astolfi; Andrea Pession
• Keywords: Hippo signaling pathway; Loss function

Abstract Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging mild hematological visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss increased neuroinflammation, whose molecular basis are still unclear. Using combination Drosophila dGBA1b loss-of-function models GD patient-derived iPSCs differentiated towards precursors mature neurons we showed that different GD- tissues cells an impairment growth mechanisms with cell death reduced proliferation. These phenotypes coupled downregulation several Hippo transcriptional targets, mainly involved tissue growth, YAP exclusion nuclei. Interestingly, knock-down GBA-KO flies rescues proliferative defect, suggesting targeting pathway can be promising therapeutic approach neuronopathic GD.