TY  - JOUR
AU  - Messelodi, Daria
AU  - Strocchi, Silvia
AU  - Bertuccio, Salvatore Nicola
AU  - Baden, Pascale
AU  - Indio, Valentina
AU  - Giorgi, Federico M
AU  - Taddia, Alberto
AU  - Serravalle, Salvatore
AU  - Valente, Sabrina
AU  - di Fonzo, Alessio
AU  - Frattini, Emanuele
AU  - Bernardoni, Roberto
AU  - Pession, Annalisa
AU  - Grifoni, Daniela
AU  - Deleidi, Michela
AU  - Astolfi, Annalisa
AU  - Pession, Andrea
TI  - Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation.
JO  - Communications biology
VL  - 6
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DZNE-2023-00458
SP  - 431
PY  - 2023
AB  - Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.
KW  - Humans
KW  - Gaucher Disease: genetics
KW  - Gaucher Disease: metabolism
KW  - Gaucher Disease: therapy
KW  - Glucosylceramidase: genetics
KW  - Glucosylceramidase: metabolism
KW  - Hippo Signaling Pathway
KW  - Neurons: metabolism
KW  - Cell Proliferation
KW  - Glucosylceramidase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10115838
C6  - pmid:37076591
DO  - DOI:10.1038/s42003-023-04813-2
UR  - https://pub.dzne.de/record/257582
ER  -