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.A combination of Drosophila dGBA1b loss-of-function models and Gaucher Disease (GD) patient-derived iPSCs reveals an impairment in GD neuronal cell growth and that Hippo pathway hyperactivation contributes to the impairment.

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

Indio, Valentina;Giorgi, Federico M;Taddia, Alberto;Valente, Sabrina;Bernardoni, Roberto;Pession, Annalisa;Astolfi, Annalisa
Penultimo
;
Pession, Andrea
Ultimo
2023

Abstract

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.A combination of Drosophila dGBA1b loss-of-function models and Gaucher Disease (GD) patient-derived iPSCs reveals an impairment in GD neuronal cell growth and that Hippo pathway hyperactivation contributes to the impairment.
2023
Messelodi, Daria; Strocchi, Silvia; Bertuccio, Salvatore Nicola; Baden, Pascale; Indio, Valentina; Giorgi, Federico M; Taddia, Alberto; Serravalle, Salvatore; Valente, Sabrina; di Fonzo, Alessio; Frattini, Emanuele; Bernardoni, Roberto; Pession, Annalisa; Grifoni, Daniela; Deleidi, Michela; Astolfi, Annalisa; Pession, Andrea
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/928098
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